KR20190032420A - Heterocyclic compounds used as FGFR inhibitors - Google Patents

Abstract

(I)The present invention relates to a heterocyclic compound, a pharmaceutical composition containing the heterocyclic compound, a method for producing the same, and a use thereof as a fibroblast growth factor receptor (FGFR) inhibitor. The compound is a heterocyclic compound as shown in formula (I), or a pharmaceutically acceptable salt, prodrug, solvate, polymorph, isomer and stable isotope derivative thereof. The invention also relates to the use of such compounds for the treatment or prevention of FGFR-mediated related diseases such as cancer, and methods of applying the compounds to treat the diseases.

(I)

Description

Heterocyclic compounds used as FGFR inhibitors

The present invention relates to heterocyclic compounds, methods of making pharmaceutical compositions containing them, and uses thereof as inhibitors of fibroblast growth factor receptor (FGFR). The compounds according to the present invention can be used to treat or prevent FGFR-mediated related diseases such as cancer.

Fibroblast growth factor (FGF) is encoded by the FGF gene family, has a different biological activity, and belongs to a family of polypeptides having related structures. So far, it has been confirmed that the FGF family has 22 members. Fibroblast growth factor receptor (FGFR) is a class of transmembrane tyrosine kinase receptors that mediate FGF signaling into the cytoplasm. Currently, four FGFRs with independent gene codes have been identified: FGFR1, FGFR2, FGFR3 and FGFR4. These are all short-chain glycoprotein molecules composed of extracellular domain, transmembrane domain and intracellular domain. Receptor-ligand interactions cause receptor dimerization and autophosphorylation, and the formation of complexes with membrane-bound proteins and cytoplasmic helper proteins, thereby mediating the conduction of multiple signals. The FGFR-FGF signaling system plays an important role in many biological processes such as cell proliferation, differentiation, migration, angiogenesis and tissue repair.

FGFR4 is the major FGF receptor subtype in the liver. Of the more than 20 fibroblast growth factors (FGF) found so far, 10 can bind to FGFR4, where only FGF19 binds specifically to FGFR4. Recent years have shown that changes such as overexpression, mutation, translocation and truncation of FGFR4 have been observed in a variety of human cancers including rhabdomyosarcoma, renal cell carcinoma, myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer and hepatocellular carcinoma Lt; / RTI >

Thus, selective inhibition of FGFR4 may be used to treat the cancer, particularly where an activated mutant of the receptor tyrosine kinase is present or that the receptor tyrosine kinase upregulated tumor is expected to be particularly susceptible to this type of inhibitor have.

It is an object of the present invention to provide a compound, its isomer, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof as shown in formula (I)

(I)

Wherein ring A and R are each independently selected from the group consisting of substituted or unsubstituted aryl and heteroaryl groups, wherein when substituted, A or R may be substituted with one or more substituents, said substituents being independently selected from the group consisting of Wherein R is selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocyclyl, aryl, heteroaryl, formyl, -C (O) R ¹ , -OR ¹ and -NR ² is selected from the group consisting of R ^3, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3 to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR 5 R 6, -C (O) R 4, -NR 5 ^{R 6, -NR 5 C (O} ) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 optionally with S (O) mNR ⁵ R ^6, -S (O) one or more substituents selected from the group consisting of mNR ⁵ R ⁶ with (optionally) And the ring;

X is selected from the group consisting of ^{CR 7 R 8, NR 7,} O and S;

Y is -C (O) - is selected from, -S (O) a group consisting of ^{m- -, -C (= NR 9} );

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl Or monocyclic aryl, alkenyl and alkynyl, wherein R ² and R ³ , or R ⁵ and R ⁶ together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl group Can be; Said R ⁷ and R ⁸ together with the C atom to which they are attached may form a 3-8 membered cycloalkyl or a 3-8 membered monocyclic heterocyclyl;

R ⁷ and R ⁸ are each independently hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, formyl, -C (O) R ¹ is selected from carboxyl, alkenyl, alkynyl, -OR ^1, and the group consisting of -NR ² R ^3, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR 5 R 6, -C ^{(O) R 4, -NR 5} R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR 5 S (O) mR ^{4, -SR 4, -NR 4 S} (O) mNR 5 R 6 , -S (O) is optionally substituted with one or more substituents selected from the group consisting of mNR ⁵ R ^6;

R ⁹ is Are independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocyclyl, aryl, heteroaryl, formyl, C (O) R ¹ , alkenyl and alkynyl, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, -OR ^4, -OC (O) ^{NR 5 R 6, -C (O} ) OR 4, -C (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 ^{C (O) NR 5 R 6} , -S (O) mR 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6, -S (O) mNR 5 R < ^{6 &} gt ;;

m is 1 or 2;

In one embodiment of the invention, there is provided a compound as shown in formula (I), an isomer thereof, a prodrug or a pharmaceutically acceptable salt thereof, wherein the compound represented by formula (I) (II): < RTI ID = 0.0 >

(II)

Z ¹ , Z ² and Z ³ are each independently selected from the group consisting of CR ^Z1 , CR ^Z2 , CR ^Z3 or N,

When Z ¹ is N, then Z ² and Z ³ are not simultaneously N;

When Z ² is N, then Z ¹ and Z ³ are not simultaneously N;

When Z ³ is N, then Z ¹ and Z ² are not simultaneously N;

R ^Z1 , R ^Z2 and R ^Z3 are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocyclyl, aryl, heteroaryl, ) R ^1, carboxyl, alkenyl, alkynyl, -OR ¹ and -NR are selected from the group consisting of R ^{2 3,} wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR 5 R 6 ^{, -C (O) R 4,} -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR 5 S ( ^{O) mR 4, -SR 4,} -NR 4 S (O) mNR 5 R 6 , -S (O) is optionally substituted with one or more substituents selected from the group consisting of mNR ⁵ R ^6;

X is selected from the group consisting of ^{CR 7 R 8, NR 7,} O and S;

Y is -C (O) - is selected from, -S (O) a group consisting of ^{m- -, -C (= NR 9} );

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl Or monocyclic aryl, alkenyl and alkynyl, wherein R ² and R ³ , or R ⁵ and R ⁶ together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl group Can be; And R ⁷ and R ⁸ together with the C atom to which they are attached may form a 3 to 8 membered cycloalkyl or 3 to 8 membered monocyclic heterocyclyl group;

R ⁷ and R ⁸ are each independently hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, formyl, -C (O) R ¹ is selected from a carboxyl, an alkenyl, alkynyl, -OR ^1, and the group consisting of -NR ² R ^3, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR 5 R 6, -C ^{(O) R 4, -NR 5} R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR 5 S (O) mR ^{4, -SR 4, -NR 4 S} (O) mNR 5 R 6 , -S (O) is optionally substituted with one or more substituents selected from the group consisting of mNR ⁵ R ^6;

R ⁹ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocyclyl, aryl, heteroaryl, formyl, C (O) R ¹ , alkenyl and alkynyl selected and wherein the group alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, -OR ^4, -OC ^{(O) NR 5 R 6,} -C (O) OR 4, -C (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, ^{-NR 4 C (O) NR 5} R 6, -S (O) mR 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , -S (O ) mNR < ⁵ > R < ^{6 &} gt ;;

If Z ¹ is CCH ₂ OH, CCH ₂ COOH, or C- (4- piperidine), compound (2-1), (2-2) and (2-3) has isomers (2-1A), ( 2-2A) and (2-3A): < RTI ID = 0.0 >

.

.

In another embodiment of the present invention there is provided a compound as shown in formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) (IIIa), (IIIb), (IIIc), (IIId), (IIIe) or (IIIf)

R ^Z1, R ^Z2, R ^Z3, R ¹⁰ and R ¹¹ are each independently hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, formyl Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halo, -C (O) R ¹ , carboxyl, alkenyl, alkynyl, -OR ¹ and -NR ² R ³ , halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C ( ^{O) NR 5 R 6, -C} (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4 ^{, -NR 5 S (O) mR} 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , and -S (O) mNR is optionally substituted with one or more substituents selected from the group consisting of ⁵ R ⁶ ;

R ⁷ is independently selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6 ^{, -C (O) OR 4,} -C (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) consisting of ^{NR 5 R 6, -S (O} ) mR 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , and -S (O) mNR ⁵ R ⁶ Lt; RTI ID = 0.0 > 1, < / RTI >

Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl Or monocyclic aryl, alkenyl and alkynyl, wherein R ² and R ³ , or R ⁵ and R ⁶ together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl group Can be; And R ⁷ and R ⁸ together with the C atom to which they are attached may form a 3 to 8 membered cycloalkyl or 3 to 8 membered monocyclic heterocyclyl group;

The R ² and R ³ , or R ⁵ and R ⁶ , together with the N atom to which they are attached, may form a 3- to 8-membered heterocyclyl group.

In a further embodiment of the invention there is provided a compound as shown in formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) Lt; RTI ID = 0.0 > (IV) < / RTI &

R ^Z1 and R ^Z2 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C7 cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl or monocyclic aryl, formyl, keto, carboxyl, cyano, oR ^1, and is selected from the group consisting of NR ² R ^3, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, hydroxy, C1-C4 alkyl , C3-C7 cycloalkyl, 4 to 6 membered heterocyclyl, aryl or heteroaryl;

R ⁷ is selected from H, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic the group consisting of aryl, wherein said alkyl, heterocyclyl , heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, - ^{C (O) OR 4, -C} (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 ^{R 6, -S (O) mR} 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , -S (O) R ⁶ from the group consisting of ⁵ mNR Optionally substituted with one or more substituents selected;

R < ¹⁰ > is independently selected from the group consisting of hydrogen, halogen, halo C1-C4 alkyl and cyano;

R ¹¹ is independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, halo C 1 -C 4 alkoxy, C 1 -C 6 alkoxy, HO-C 1 -C 4 alkoxy, cyano, NR ² R ³ , C 1 -C 4 alkoxy C 1 -C 4 alkoxy, C1-C4 alkoxy halo C1-C4 alkoxy;

R ¹ , R ² and R ³ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, Alkylthiol, and haloalkoxy substituted with hydroxy at any position;

R ⁴ , R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, Alkynyl, R ² and R ³ , or R ⁵ and R ⁶ together with the N atom to which they are attached may form a 3- to 7-membered heterocyclyl group; And R ⁷ and R ⁸ together with the C atom to which they are attached may form a 3- to 8-membered cyclic group or a 3- to 8-membered monocyclic heterocyclic group.

In a further embodiment of the invention there is provided a compound as shown in formula (I), an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) Lt; RTI ID = 0.0 > (V) < / RTI >

R ^Z1 and R ^Z2 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C7 cycloalkyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl or monocyclic aryl, Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C4 alkyl, 5-6 membered heterocyclyl, aryl or heteroaryl ≪ RTI ID = 0.0 > 1, < / RTI >

R ⁷ is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 3-6 cycloalkyl wherein said alkyl or cycloalkyl group is optionally substituted with one or more groups selected from the group consisting of C 1 -C 3 alkyl and 4-6 membered monocyclic heterocyclyl Optionally substituted with one or more of the above substituents;

R ¹¹ is selected from the group consisting of NR ² R ³ , C ¹ -C 3 alkoxy and -O (CH ₂ ) _0-1 -R ⁴ ; Wherein R ⁴ is independently selected from the group consisting of hydrogen, HO-C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, -OR ^5, -OC (O) ^{NR 5 R 6, -C (O} ) OR 5, -C (O) NR 5 R 6, -C (O) R 5, -NR 5 R 6, -NR 5 C (O) R 6, -NR 7 ^{C (O) NR 5 R 6} , -S (O) mR 5, -NR 5 S (O) mR 6, -SR 5, -NR 7 S (O) mNR 5 R 6 , and -S (O) mNR ⁵ R < ^{6 &} gt ;; R ² and R ³ are independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with at least one substituent selected from the group consisting of halogen, cyano, C1-C8 alkyl, C3-C8 cyclo , 3- to 8-membered ^{heterocyclyl, -OR 5, -OC (O)} NR 5 R 6, -C (O) OR 5, -C (O) NR 5 R 6, -C (O) R 5, - ^{NR 5 R 6, -NR 5 C} (O) R 6, -NR 7 C (O) NR 5 R 6, -S (O) mR 6, -NR 5 S (O) mR 6, -SR 5, - NR ⁷ S (O) mNR ⁵ R ⁶ and -S (O) mNR ⁵ R ⁶ ;

R ⁴ , R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, Alkynyl, R ² and R ³ , or R ⁵ and R ⁶ together with the N atom to which they are attached may form a 3- to 7-membered heterocyclyl group; And R ⁷ and R ⁸ together with the C atom to which they are attached may form a 3- to 8-membered cyclic group or a 3- to 8-membered monocyclic heterocyclic group.

Exemplary compounds according to the present invention include, but are not limited to, the following: or tautomers, mesomers, racemates, enantiomers, diastereomers, mixtures thereof and pharmaceutically acceptable salts thereof Does not:

The compounds according to the present invention are effective inhibitors of FGFR, particularly effective selective inhibitors of FGFR4. Accordingly, the compounds according to the present invention may be used to treat or prevent FGFR4 mediated diseases, including, but not limited to, FGFR mediated diseases, particularly cancer and inflammatory diseases. The compounds according to the present invention can be used to treat or prevent cancer, such as rhabdomyosarcoma, renal cell carcinoma, myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer and hepatocellular carcinoma. The compounds according to the invention are particularly capable of treating or preventing liver cancer, and in particular hepatocellular carcinoma. Tumors with activated mutants of receptor tyrosine kinases or with unregulated receptor tyrosine kinases are particularly susceptible to this type of inhibitor.

As selective inhibitors of FGFR4, the compounds according to the present invention have lower side effects.

The present invention also relates to pharmaceutical compositions comprising a compound as shown in formula (I) or an isomer, prodrug, stable isotope derivative thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier , Diluents and excipients.

The present invention also encompasses a method of making the pharmaceutical composition, including, for example, admixing a compound according to the present invention with a pharmaceutically acceptable carrier, diluent and excipient. Pharmaceutical compositions according to the present invention can be prepared by conventional methods in the art.

Another aspect of the present invention relates to the use of a compound as shown in formula (I) or an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for the treatment or prevention of FGFR and particularly FGFR4 mediated diseases such as tumor or inflammatory diseases , Stable isotope derivatives or pharmaceutically acceptable salts thereof, and the use of pharmaceutically acceptable carriers, diluents and excipients therefor.

Another aspect of the present invention relates to the use of a compound as shown in formula (I) or a tautomer, mesomer, racemate, racemate, racemate, racemate, or tautomer thereof in the manufacture of a medicament for the treatment and / Enantiomers, diastereoisomers, mixtures thereof and pharmaceutically acceptable salts thereof, or the use of such pharmaceutical compositions.

According to the present invention, the drug may be in any dosage form, including, but not limited to, tablets, capsules, liquors, lyophilized preparations and injections. The pharmaceutical preparations according to the invention may be administered in the form of dosage units containing a predetermined amount of active ingredient per dosage unit. Such unit may be, for example, 0.5 mg to 1 g, preferably 1 mg to 700 mg, particularly preferably 5 mg to 300 mg, depending on the disease to be treated, the mode of administration, and the age, May contain a compound according to the invention, or the pharmaceutical preparation may be administered in the form of a dosage unit containing a predetermined amount of active ingredient per dosage unit. Preferred dosage unit formulations comprise a daily dose or divided doses or active ingredients as specified above of the corresponding fractions. In addition, pharmaceutical preparations of this type can be prepared by methods well known in the pharmaceutical arts.

The pharmaceutical preparations according to the present invention may be administered orally or parenterally (including subcutaneous, intramuscular, intravenous, oral, sublingual, topical ≪ / RTI > intradermally or intradermally). By using all methods known in the pharmaceutical art, such preparations can be prepared, for example, by combining the active ingredients with one or more excipients or one or more adjuvants.

Pharmaceutical formulations suitable for oral administration may be presented as discrete units such as capsules or tablets; Powder or granules; Solutions or suspensions in aqueous or non-aqueous liquids; Or as an oil-in-water liquid emulsion or a water-in-oil liquid emulsion.

The invention also relates to a method of treating or preventing FGFR and in particular an FGFR4 mediated disease (e.g., a tumor or inflammatory disease) comprising administering a therapeutically effective amount of a compound as shown in formula (I) A prodrug, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent or excipient as described herein, to a patient in need thereof.

A further aspect of the invention relates to a compound as shown in formula (I) or an isomer thereof, a prodrug thereof, or a pharmaceutically acceptable salt thereof, for use in the treatment and / or prophylaxis of FGFR and particularly FGFR4 mediated diseases, A stable isotope derivative or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable carriers, diluents and excipients thereof.

Another aspect of the present invention relates to the use of a compound as shown in formula (I) or a tautomer, mesomer, racemate, enantiomer, diastereomer, racemate, racemate, racemate or racemate thereof for the treatment and / Mixtures thereof and pharmaceutically acceptable salts thereof.

Manufacturing Reaction Formula

The present invention also provides a process for preparing said compound.

Scheme 1

Step 1: R ^Z2 and R ⁷ in the structural formula of the compound (VI-1) correspond to those in the formula (VI), and the compound (VI-2) (Diphenylphosphine) ferrocene as a ligand and triethylamine as an alkali, and R ^Z2 and R ⁷ in the compound (VI-2) are synthesized from a compound (VI-1) Lt; RTI ID = 0.0 > (VI). ≪ / RTI >

Step 2: A mixture of reducing agent, the ester of the (VI-2) (sodium borohydride) was reduced by the compound synthesized (VI-3) and Compound (VI-3) R ^Z2 and R ⁷ in the structural formula (VI). ≪ / RTI >

Step 3: is a substituted hydroxy group in the structural formula (VI-3), Compound (VI-4) is synthesized using phosphorus tribromide as a reaction agent, the compound (VI-4) of R ^Z2 and R ⁷ are in Lt; RTI ID = 0.0 > (VI). ≪ / RTI >

Step 4: The bromide in the formula (VI-4) is replaced with a nucleophilic reagent (morpholin-3-one, 4-methylpiperazin-2-one and the like) and the compound (VI-5) Is synthesized using an alkali (sodium hydride), and R ^Z2 and R ⁷ in the compound (VI-5) correspond to those in the formula (VI).

Step 5: R ^Z2 and R ⁷ in compound (VI-5) are consistent with those in formula (VI) wherein the amino protecting group is removed by an acid (trifluoroacetic acid) And purified to give compound (VI).

Scheme 2

Step 1: R ^Z1 , R ^Z2 and R ⁷ in the structural formula of the compound (VI) are the same as those in the formula (IV), and the compound (VI) is used as a deprotonating agent with an alkali (lithium hexamethyldisilazide) And activated with an acylating agent (diphenyl carbonate or phenyl chloroformate) to synthesize compound (VII).

Step 2: R ¹⁰ and R ¹¹ on 2-aminopyridine are consistent with those in formula (IV), the phenol group in compound (VII) is substituted and the alkaline (lithium hexamethyldisilazide) is used as the deprotonating agent (VIII) is synthesized, and R ^Z1 , R ^Z2 and R ⁷ in the compound (VIII) correspond to those in the formula (IV).

Step 3: R ^Z1 , R ^Z2, and R ⁷ in compound (VIII) are consistent with those in formula (IV) wherein the acetal protecting group is removed by an acid, alkalized using sodium bicarbonate, (IV) can be obtained.

Scheme 3

Step 1: R ^Z2 and R ⁷ in the formula of compound (VI-1) are consistent with those in formula (IV), compound (VI-5) is palladium- (VI-1), wherein the catalyst is [1,1'-bis (diphenylphosphino) ferrocene] palladium chloride, the alkali is potassium carbonate, and the compound R ^Z1 , R ^Z2 and R ¹⁰ are as defined in formula (IV). Step 2, Step 3, and Step 4 are illustrated in Scheme 2.

Justice

Unless stated to the contrary, the following terms used in the description and the claims have the following meanings.

As used herein, the expression " Cx-y " denotes a range of number of carbon atoms, wherein both x and y are integers. For example, C3-8 cycloalkyl represents a cycloalkyl group having 3 to 8 carbon atoms, -C0-2 alkyl represents an alkyl group having 0 to 2 carbon atoms, wherein -C0 alkyl represents a single chemical bond Quot;

The term " alkyl " as used herein includes saturated and aliphatic hydrocarbon groups, such as linear and branched groups having from 1 to 20 carbon atoms, for example, from 1 to 18 carbon atoms, from 1 to 12 carbon atoms, Refers to a linear and branched group having from 1 to 6 carbon atoms or from 1 to 4 carbon atoms. Non-limiting examples are methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, , 2-dimethylpropyl, 1-ethylpropyl, 2-methylbutyl, 3-methylbutyl, n-hexyl, Butyl, 1,2-dimethylbutyl, 2,2-dimethylbutyl, 1,3-dimethylbutyl, 2-ethylbutyl, and various branched isomers thereof. Alkyl can be substituted or unsubstituted.

The term " cycloalkyl " as used herein refers to a cyclic carbon atom having from 3 to 12 cyclic carbon atoms, such as from 3 to 12, from 3 to 10, from 3 to 8, or from 3 to 6 cyclic carbon atoms, Quot; refers to a saturated or partially unsaturated monocyclic or polycyclic hydrocarbon group containing 5, 6, 7, 8 or 8 membered rings. Non-limiting examples of monocyclic cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cyclohexadienyl, cycloheptyl, cycloheptatrienyl, cyclooctyl, and the like do. Cyclyl can be substituted or unsubstituted.

The term " heterocyclyl, " as used herein, refers to a saturated or unsaturated, saturated or unsaturated, saturated or partially saturated Or a partially unsaturated monocyclic or polycyclic group in which one or more ring atoms are optionally replaced by nitrogen, oxygen or S (O) m, where the ring part of -OO-, -OS- or -SS-, m is an integer of 0 to 2), and the remaining ring atoms are carbon. Preferably 3 to 12 ring atoms of which from 1 to 4 are heteroatoms. More preferably, the heterocyclyl ring contains 3 to 10 ring atoms. Most preferred are 5-membered rings or 6-membered rings in which 1 to 4 are heteroatoms, more preferably 1 to 3 heteroatoms, most preferably 1 to 2 heteroatoms. Non-limiting examples of monocyclic heterocyclyl include pyrrolidinyl, piperidyl, piperazinyl, morpholinyl, thiomorpholinyl, fomopiperazinyl, and the like. The polycyclic heterocyclic groups include spirocyclic, fused and bridged cyclic heterocyclyl groups.

The term " spiroheterocyclic group " as used herein refers to a 5 to 20 membered polycyclic heterocyclic group having one atom (referred to as a spiro atom) shared between monocyclic rings wherein one of the ring atoms Is a heteroatom selected from the group consisting of nitrogen, oxygen or S (O) m wherein m is an integer from 0 to 2, and the remainder of the ring atoms are carbon. They may contain one or more double bonds, but none of the rings have a completely conjugated pi (pi) electron system. These are preferably 6 to 14 atoms, more preferably 7 to 10 atoms. Depending on the number of spiro atoms shared between the rings, the spirocyclyl groups are divided into monospiroheterocyclyl, bispyroheterocyclyl or polispyroheterocyclyl, and the spirocyclyl groups are preferably monospiracyclic and bispyrocyclyl, Reel, preferably 4/4, 4/5, 4/6, 5/5 or 5/6 monosporicyclyl. Non-limiting examples of spirocyclyl include:

및

^.

And

^.

The term " fused heterocyclyl " as used herein refers to a 5- to 20-membered polycyclic heterocyclyl group wherein each ring in the system shares a pair of adjacent atoms with another ring in the system, (O) m, where m is an integer from 0 to 2, with one or more of the ring atoms being optionally substituted with one or more substituents independently selected from the group consisting of hydrogen, And the remaining ring atoms are carbon. These are preferably 6 to 14 atoms, more preferably 7 to 10 atoms. Depending on the number of rings, they may be split into bicyclic, tricyclic, tetracyclic or polycyclic fused heterocyclyl, and the fused heterocyclyl groups are preferably bicyclic or tricyclic, more preferably 5 < RTI ID = 0.0 > 5-membered, or 5-membered / 6-membered bicyclic fused heterocyclyl. Non-limiting examples of fused heterocyclyls include:

및

.

And

.

The heterocyclyl ring can be fused to an aryl, heteroaryl or cycloyl ring, wherein the ring connected to the parent structure is a heterocyclyl group, and non-limiting examples include:

및

, 등.

And

, Etc.

The heterocyclyl group may be substituted or unsubstituted.

The term " aryl " as used herein refers to an all-carbon monocyclic or condensed polycyclic (i.e., ring that shares adjacent carbon atom pairs) groups of 6 to 14 members and a polycyclic That is, a ring having adjacent carbon atom pairs) group, preferably 6 to 10 atoms, such as phenyl and naphthyl, and most preferably phenyl. The aryl ring may be fused to a heteroaryl, heterocyclyl or cycloyl ring, wherein the ring connected to the parent structure is an aryl ring, and non-limiting examples include:

및

.

And

.

Aryl can be substituted or unsubstituted.

The term " heteroaryl " as used herein refers to a heteroaromatic system containing from one to four heteroatoms and from five to fourteen ring atoms, wherein the heteroatoms include oxygen, sulfur, and nitrogen. The heteroaryl is preferably a 5- to 10-membered ring, more preferably a 5-membered or 6-membered ring such as furyl, thienyl, pyridyl, pyrrolyl, N-alkylpyrrolyl, pyrimidinyl, Tetrazolyl, oxazolyl, and i-oxazolyl. The heteroaryl ring can be fused to an aryl, heterocyclyl or cycloyl ring, wherein the ring connected to the parent structure is a heteroaryl ring, and non-limiting examples include:

및

.

And

.

Heteroaryl may be substituted or unsubstituted.

The term " halogen " as used herein refers to fluorine, chlorine, bromine or iodine.

The term " cyano " as used herein refers to -CN.

The term " alkenyl " as used herein refers to a linear, branched or cyclic nonaromatic hydrocarbon group containing at least one carbon-carbon double bond, wherein one to three carbon-carbon double bonds may be present, May be present in one carbon-carbon double bond, such as vinyl, propenyl, butenyl, 2-methylbutenyl and cyclohexenyl. The alkenyl group may be substituted. The term " C2-4 alkenyl " refers to an alkenyl having 2 to 4 carbon atoms.

The term " alkynyl " as used herein refers to a linear, branched or cyclic hydrocarbon group containing at least one carbon-carbon triple bond wherein one to three carbon-carbon triple bonds may be present, Carbon triple bonds may be present, such as acetenyl, propynyl, butynyl and 3-methylbutynyl. The term " C2-4 alkynyl " refers to alkynyl having 2 to 4 carbon atoms.

The term " alkoxy " as used herein refers to cyclic or non-cyclic alkyl groups, such as alkyloxy, cycloalkyloxy, and heterocycloalkyloxy, having the number of carbon atoms connected by an oxo bridge. Thus, " alkoxy " includes the above definitions of alkyl, heterocycloalkyl, and cycloalkyl. The terms " optional " and " optionally " mean that the subsequently described event or circumstance may but need not occur, and includes, or does not occur, the event or circumstance . For example, " heterocyclyl optionally substituted by alkyl " means that the alkyl may be present, but is not necessarily present, and includes heterocyclyl substituted by alkyl and not substituted by alkyl.

The term " substituted " as used herein refers to that at least one hydrogen atom in the group, preferably at most 5, more preferably 1 to 3, hydrogen atoms are independently substituted with the corresponding number of substituents. It is to be understood that the substituents are located only at their possible chemical positions and that the ordinary skilled artisan can determine (possibly experimentally or theoretically) possible or impossible substitutions without much effort. For example, an amino or hydroxy group with free hydrogen may be unstable when combined with a carbon atom having an unsaturated (e.g., olefinic) linkage.

The term " pharmaceutical composition " as used herein is intended to encompass a pharmaceutical composition comprising one or more of the compounds described herein or a physiologically / pharmaceutically acceptable salt or prodrug and other chemical components as well as physiologically / pharmaceutically acceptable carriers and excipients Represents a mixture with other ingredients. The purpose of the pharmaceutical composition is to promote drug administration to the organism, to facilitate absorption of the active constituents, and thus to exert biological activity.

In the present invention, "room temperature" refers to 15 to 30 ° C.

The term " stable isotope derivatives " herein includes: isotopically-substituted derivatives obtained by substituting any of the hydrogen atoms in formula (I) with 1 to 5 deuterium atoms, Isotopically substituted derivatives obtained by substituting 1 to 3 carbon atoms of the carbon atom of the formula (I) or isotopes obtained by substituting one to three oxygen-18 atoms of any oxygen atom in the formula (I) Substituted derivatives thereof.

&Quot; Pharmaceutically acceptable salts, " as described in Berge, et al., J. Pharm. Sci. , 66, 1-19 (1977)), and it is believed that the salts are essentially non-toxic and can provide the desired pharmacokinetic properties, palatability, absorption, distribution, metabolism or excretion Is apparent to pharmaceutical chemists.

The pharmaceutically acceptable salts according to the present invention can be synthesized by conventional chemical methods.

Generally, the preparation of a salt can be accomplished by reacting an equivalent amount of free alkali or acid or an excess of acid (inorganic or organic acid) or alkali with the corresponding chemical equivalent in a suitable solvent or solvent composition.

&Quot; Prodrug " as described in the present invention refers to a compound that is metabolized in vivo and then converted to the original active compound. Typically speaking, the prodrug is an inert substance or has a lower activity than the active parent compound, but can provide convenient handling and administration or can improve the metabolism properties.

&Quot; Isomeric " of the present invention means that the compound of formula (I) according to the invention may have asymmetric centers and racemates, racemic mixtures and single diastereomers, wherein the stereoisomers and geometric isomers All such isomers are included in the present invention. The geometric isomers include cis- and trans-isomers.

The term " tumor " as used herein includes benign and malignant tumors, such as cancer.

The term " cancer " herein encompasses a variety of malignancies, particularly those involving FGFR and particularly FGFR4, including but not limited to rhabdomyosarcoma, renal cell carcinoma, myeloma, breast cancer, gastric cancer, colon cancer, bladder cancer, pancreatic cancer and hepatocellular carcinoma .

The term " inflammatory disease " as used herein refers to any inflammatory disease involving FGFR and particularly FGFR4.

Example

The present invention will be further illustrated by the following examples, which, however, are not intended to limit the scope of the embodiments described. In the following examples, experimental methods without the specific conditions mentioned are selected according to conventional methods and conditions or according to the manufacturing instructions.

The structures of all compounds according to the invention can be confirmed by nuclear magnetic resonance (1 H NMR) and / or mass spectrometry detection (MS).

^{The 1} H NMR chemical shift (δ) is reported as PPM (unit: 10 ^-6 PPM). NMR is performed by a Bruker AVANCE-400 spectrometer. Suitable solvents include deuterated chloroform (CDCl ₃ ), deuterated methanol (CD ₃ OD) and deuterated dimethyl sulfoxide (DMSO-d ⁶ ) and have tetramethylsilane (TMS) as internal standard.

The low resolution mass spectral image (MS) shows the gradient elution conditions I: 0: 95% solvent A1 and 5% solvent B1, 1-2: 5% solvent A1 and 95% solvent B1; 2.01-2.50: Determined by an Agilent 1260 HPLC / 6120 mass spectrometer using Agilent ZORBAX XDB-C18, 4.6 x 50 mm, 3.5 μm in 95% solvent A1 and 5% solvent B1. Percentages are volume percentages of a particular solvent based on the total solvent volume. Solvent A1: 0.01% aqueous formic acid solution; Solvent B1: a 0.01% formic acid solution in acetonitrile; Percentage is the volume percentage of solute based on solution.

The thin silica gel plate is a Yantai Yellow Sea HSGF254 or Qingdao GF254 silica gel plate. Silica gels of Yantai Yellow Sea 100-200 or 200-300 mesh are generally used as supports in column chromatography.

The known starting materials of the present invention can be synthesized by or in accordance with methods known in the art or can be synthesized according to methods known in the art or can be synthesized by methods known in the art such as Acros Organics, Aldrich Chemical Company, Accela ChemBio Inc., Shanghai Bide Pharmatech, Shanghai Aladdin Chemistry, Shanghai Meryer Chemistry , Accelerating Chemistry, and the like.

In the examples, unless otherwise stated, the solvents used in the reactions are all anhydrous solvents, wherein anhydrous tetrahydrofuran is commercially available tetrahydrofuran, sodium blocks are used as dehydrating agents, and benzophenone Is used as an indicator and the solution is refluxed under the protection of nitrogen gas until it turns indigo, which is collected by distillation and is stored at room temperature under the protection of nitrogen gas and the other anhydrous solvent is obtained from Aladdin Chemistry and Accelerating Chemistry , And the transfer and use of all anhydrous solvents will be carried out under the protection of nitrogen gas unless specifically mentioned.

In the examples, the reactions are all carried out under an argon atmosphere or a nitrogen atmosphere unless specifically mentioned.

An argon atmosphere or nitrogen atmosphere refers to the reaction flask being connected to an argon or nitrogen balloon having a volume of about 1 L.

The hydrogen atmosphere refers to the reaction flask being connected to a hydrogen balloon having a volume of about 1 L.

The carbon monoxide atmosphere refers to the reaction flask being connected to a carbon monoxide balloon having a volume of about 1 L.

In hydrogenation, the reaction is usually vacuum treated and filled with hydrogen gas, which is repeated three times.

The reaction temperature is room temperature, and the temperature range is from 15 캜 to 30 캜, unless specifically mentioned.

The reaction process in the examples is monitored using a thin layer chromatography method (TLC). The development system used in the reaction comprises A: dichloromethane and methanol system, and B: petroleum ether and ethyl acetate system, wherein the volume ratio of the solvents is adjusted according to the polarity of the compound.

The eluent system for column chromatography and the development system for thin layer chromatography used in the purification of the compounds include A: dichloromethane and methanol systems, and B: petroleum ether and ethyl acetate systems, wherein the volume ratio of solvents is It is adjusted according to the polarity of the compound, and a small amount of triethylamine and an acid or alkali reagent, etc. may also be added for adjustment.

Example 1

2-yl) -1- (2-methoxyethyl) amino) pyrid-

Step 1

6-chloro-2-hydroxymethylpyridine

Compound Methyl 6-chloro-2-pyridine Formate 1a (1.00 g, 5.85 mmol), sodium borohydride (0.38 g, 9.95 mmol) and ethanol (15 mL) were mixed and stirred at room temperature for 6 hours. The mixture was quenched with 30 mL of water, extracted with ethyl acetate (50 mL x 2), and the organic phase washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure to give the target product 6-chloro-2-hydroxymethylpyridine 1b (0.70 g, yellow oil) in 84% yield Respectively. The product was used directly in the subsequent reaction without purification.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.68 (dd, J = 8.0, 7.6 Hz, 1H), 7.27 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 7.6 Hz, 1H), 4.76 (d, J = 5.2 Hz, 2H), 3.07 (t, J = 5.6 Hz, 1H).

Step 2

(6- (methylamino) pyrid-2-yl) methanol

The compound 6-chloro-2-hydroxymethylpyridine 1b (1.50 g, 10.5 mmol) was mixed with methylamine (15 mL, 30% solution in ethanol) and stirred at 100 ° C for 48 hours. The mixture was cooled to room temperature and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 10: 1 to 1: 2) to give the target product 6- (methylamino) pyrid- Oil) in 48% yield.

MS m / z (ESI): 139 [M + 1].

Step 3

6- (methylamino) methylpyridine aldehyde

A mixture of compound 1c (0.60 g, 4.35 mmol), manganese dioxide (3.78 g, 43.5 mmol) and dichloromethane (15 mL) was mixed at 40 ° C for 16 h Lt; / RTI > The mixture was cooled to room temperature and filtered. The filtrate was eluted under reduced pressure to give the target product 6- (methylamino) methylpyridine aldehyde 1d (0.50 g, yellow solid) in 72% yield.

MS m / z (ESI): 137 [M + 1].

Step 4

6- (1,3-dioxolan-2-yl) -N -methylpyridin-2-amine

(0.80 g, 5.95 mmol), ethylene glycol (1.80 g, 29.7 mmol), p-toluenesulfonic acid (0.10 g, 0.60 mmol), 4A molecular sieve (0.2 g) and toluene (15 mL) were mixed and stirred at 120 ° C for 5 hours. The mixture was cooled to room temperature, the mixture was diluted with 30 mL of water, extracted with ethyl acetate (50 mL x 2), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 6: 1 to 2: 1) to give the target product 6- (1,3-dioxolan-2-yl) -N -methylpyridin- -Amine (0.60 g, yellow solid) in 57% yield.

MS m / z (ESI): 181 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 7.51 (t, J = 8.0 Hz, 1H), 6.83 (d, J = 7.2 Hz, 1H), 6.39 (d, J = 8.0 Hz, 1H), 5.72 (s (M, 2H), 2.93 (d, J = 4.8 Hz, 3H), 4.66 (br s, 1H), 4.20-4.14 (m, 2H), 4.09-4.

Step 5

Phenyl (6- (1,3-dioxolan-2-yl) pyrid-2-yl) (methyl) aminocarboxylate

The compound 6- (1,3-dioxolan-2-yl) - N - methyl-2-amine 1e (54 mg, 0.30 mmol) , diphenyl carbonate (1.28 g, 0.60 mmol), lithium hexamethyldisilazane Zaid (0.41 mL, 0.41 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (3 mL) were mixed and stirred at 0 ° C for 2 hours. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 4: 1) to give the target product phenyl (6- (1,3-dioxolan-2-yl) pyrid- ) Aminocarboxylate (60 mg, white solid) in 67% yield.

MS m / z (ESI): 301 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 7.96-7.94 (m, 1H), 7.74-7.70 (m, 1H), 7.45-7.32 (m, 2H), 7.40-7.38 (m, 1H), 7.28-7.25 (m, 2 H), 3.67 (s, 3 H), 4.20-7.17 (m, 2 H), 5.87 (s,

Step 6

Yl) -3- (4-chloro-5-cyanopyrid-2-yl) -1-methylurea

(60 mg, 0.20 mmol), 6-amino-4-chloronicotinonitrile (prepared according to the method described in Example 1), and phenyl (6- (1,3-dioxolan- 76 mg, 0.50 mmol), lithium hexamethyldisilazide (0.4 mL, 0.4 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 2 hours. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 30: 1) to give the target product 1- (6- (1,3-dioxolan-2-yl) pyrid- - (4-chloro-5-cyanopyrid-2-yl) -1-methylurea (22 mg, white solid) in 31% yield.

MS m / z (ESI): 360 & 362 [M + 1]

^{1 H NMR (400 MHz, DMSO-} d 6) δ 13.44 (s, 1H), 8.87 (s, 1H), 8.33 (s, 1H), 8.04-8.00 (m, 1H), 7.42 (d, J = 8.4 1H), 7.36 (d, J = 7.6Hz, 1H), 5.82 (s, 1H), 4.24-4.21 (m, 2H), 4.04-4.01 (m, 2H), 3.44 (s,

Step 7

3- (5-cyano-4 - ((2-methoxyethyl) amino) pyrid-2- Yl) -1-methylurea

1 g of the compound 1- (6- (1,3-dioxolan-2-yl) pyrid-2-yl) -3- (4-chloro-5-cyanopyrid- 22 mg, 0.06 mmol), 2-methoxyethylamine (14 mg, 0.18 mmol), diisopropylethylamine (24 mg, 0.18 mmol) and N, 0.0 > C < / RTI > for 16 hours. The mixture was diluted with 10 mL of water, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 2: 1) to give the target product 1- (6- (1,3-dioxolan-2-yl) pyrid- Yl) -1-methylurea (10 mg, white solid) in a yield of 41%. ≪ RTI ID = 0.0 > 3- (5-

MS m / z (ESI): 399 [M + 1].

Step 8

2-yl) -1- (2-methoxyethyl) amino) pyrid-

The compound 1- (6- (1,3-dioxolan-2-yl) pyrid-2-yl) -3- (5- (10 mg, 0.025 mmol), hydrochloric acid (0.5 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 6 hours . The mixture was quenched with saturated sodium carbonate solution, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 20: 1) to give the target product 3- (5-cyano-4 - ((2- methoxyethyl) amino) ) -1- (6-formylpyrid-2-yl) -1-methylurea (8 mg, white solid) in 90% yield.

MS m / z (ESI): 355 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.03 (s, 1H), 10.18 (s, 1H), 8.21 (s, 1H), 8.02-7.98 (m, 1H), 7.75 (d, J = 7.6 Hz, 1H), 7.59 (s, 1H ), 7.36 (d, J = 8.4 Hz, 1H), 5.82 (s, 1H), 3.66 (t, J = 4.8 Hz, 2H), 3.56 (s, 3H), 3.52- 3.50 (m, 2 H), 3.44 (s, 3 H).

Example 2

3- (6-Chloropyrimidin-4-yl) -1- (6-formylpyrid-2-yl)

Example 2 was synthesized with reference to the operating steps of Example 1, with the exception that 6-amino-4-chloronicotinonitrile was replaced with 6-chloropyrimidin-4-amine in step 6.

MS m / z (ESI): 292 & 294 [M + l]

^{1 H NMR (400 MHz, CDCl} 3) δ 13.51 (s, 1H), 10.18 (s, 1H), 8.67 (s, 1H), 8.25 (s, 1H), 8.02 (dd, J = 8.4, 7.6 Hz, 1H), 7.79 (d, J = 7.6 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 3.59 (s, 3H).

Example 3

3- (5-cyanopyrid-2-yl) -1- (6-formylpyrid-2-yl)

Example 3 was synthesized with reference to the operating steps of Example 1, with the exception that 6-amino-4-chloronicotinonitrile was replaced with 6-aminonicotinonitrile in Step 6.

MS m / z (ESI): 282 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.49 (s, 1H), 10.19 (s, 1H), 8.60 (s, 1H), 8.34 (d, J = 7.6 Hz, 1H), 8.03 (dd, J = 8.8, 7.6 Hz, 1H), 7.95-7.93 (m, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.39 (d, J = 8.8 Hz, 1H), 3.59 (s,

Example 4

Cyanopyrid-2-yl) -1- (6-formylpyrid-2-yl) -1-methylurea

Example 4 was synthesized with reference to the operating steps of Example 1, with the exception that 6-amino-4-chloronicotinonitrile was replaced with 4-chloropyridin-2-amine in step 6.

MS m / z (ESI): 291 & 293 [M + l]

^{1 H NMR (400 MHz, CDCl} 3) δ 13.09 (s, 1H), 10.19 (s, 1H), 8.29 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 5.2 Hz, 1H), 8.00 (dd, J = 8.4, 7.2 Hz, 1H), 7.74 (d, J = 7.2 Hz, 1H), 7.37 (d, J = 8.4 Hz, 1H), 7.03 (dd, J = 5.2,2.0 Hz, 1H) , 3.58 (s, 3 H).

Example 5

2-yl) -1- (6-formylpyrid-2-yl) -1-methylurea

Example 5 was synthesized with reference to the operating steps of Example 1, except that in Step 7, 2-methoxyethylamine was replaced with isopropylamine.

MS m / z (ESI): 339 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.00 (s, 1H), 10.18 (s, 1H), 8.20 (s, 1H), 8.02-7.97 (m, 1H), 7.76-7.74 (m, 1H), 7.60 (s, 1H), 7.57-7.54 (m, 1H), 7.36 (d, J = 8.4 Hz, 1H), 3.92-3.89 (m, 1H), 3.57 (s, 3H), 1.34 (d, J = 6.4 Hz, 6H).

Example 6

2-yl) -1- (6-formylpyrid-2-yl) -1-methylurea

Step 1

6-Amino-4-isopropoxynicotinonitrile

The compound 6-amino-4-chloro-nicotinoyl nitrile 6a (46 mg, 0.30 mmol) , isopropanol (90 mg, 1.50 mmol), sodium hydride (72 mg, 1.80 mmol, 60 % mineral oil mixture), and N - methylpiperidin (1.5 mL) were mixed and stirred at 70 < 0 > C for 24 hours. The mixture was cooled to room temperature, the mixture was quenched with 20 mL of water, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 6-amino-4-isopropoxynicotinonitrile 6b (16 mg, yellow solid) .

MS m / z (ESI): 178 [M + 1].

Step 2

Yl) -3- (5-cyano-4-isopropoxypyrid-2-yl) -1-methylurea

Example 6c was synthesized with reference to the operating steps in Step 6 of Example 1, with the exception that 6-amino-4-chloronicotinonitrile was replaced by 6-amino-4-isopropoxynicotinonitrile, Synthesis of 1- (6- (1,3-dioxolan-2-yl) pyrid-2-yl) -3- (5-cyano-4-isopropoxypyrid- Urea 6c (8 mg, white solid) in 46% yield.

MS m / z (ESI): 384 [M + 1].

Step 3

2-yl) -1- (6-formylpyrid-2-yl) -1-methylurea

3- (5-cyano-4 - ((2-methoxyethyl) amino) pyrid-2- Yl) -3- (5-cyano-4-isopropoxypyrid-2-yl) -Yl) -l-methylurea, < / RTI > Example 6 was synthesized according to the procedure in Example 8 step 8 to yield the target product 3- (5-cyano-4-isopropoxypyridine Yl) -1-methylurea 7 (5 mg, white solid) in 71% yield.

MS m / z (ESI): 340 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.33 (s, 1H), 10.19 (s, 1H), 8.38 (s, 1H), 8.02 (dd, J = 8.0, 7.6 Hz, 1H), 7.96 (s, 1H), 7.77 (d, J = 7.6 Hz, 1H), 7.38 (d, J = 8.0 Hz, 1H), 4.88-4.86 (m, 1H), 3.58 (s, 3H), 1.48 (d, J = 6.0 Hz, 6H).

Example 7

2-yl) -1- (6-formylpyrid-2-yl) -1-methylurea

Example 7 was synthesized with reference to the operating steps of Example 6 except that in Step 1 isopropanol was replaced by 2-methoxyethylene glycol amine.

MS m / z (ESI): 356 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.38 (s, 1H), 10.18 (s, 1H), 8.40 (s, 1H), 8.02 (dd, J = 8.4, 7.2 Hz, 1H), 7.99 (s, 1H), 7.77 (d, J = 7.2 Hz, 1H), 7.38 (d, J = 8.4 Hz, 1H), 4.38 (t, J = 4.8 Hz, 2H), 3.86 (t, J = 4.8 Hz, 2H) , 3.58 (s, 3H), 3.51 (s, 3H).

Example 8

2-yl) -1- (4-formylpyrimidin-2-yl) -1-methylurea

Step 1

4- (dimethoxymethyl) pyrimidin-2-amine

1,1-Dimethoxy- N, N -dimethylmethylamine 8a (4.90 g, 41.36 mmol) was mixed with 1,1-dimethoxypropan-2-one (4.90 g, 41.36 mmol). The mixture was stirred at 100 < 0 > C for 16 hours and eluted under reduced pressure. The residue was mixed with guanidine hydrochloride (4.30 g, 45.00 mmol), sodium hydroxide (1.80 g, 45.00 mmol) and water (15 mL) and stirred at room temperature for 48 hours. Filtration was carried out to obtain the target product 4- (dimethoxymethyl) pyrimidin-2-amine 8b (2.00 g, white solid) in 27% yield.

MS m / z (ESI): 170 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 8.36 (d, J = 4.8 Hz, 1H), 6.87 (d, J = 5.2 Hz, 1H), 5.16 (s, 1H), 5.15 (brs, 2H), 3.42 (s, 6 H).

Step 2

4- (dimethoxymethyl) -N -methylpyrimidin-2-amine

The compound 4- (dimethoxymethyl) pyrimidin-2-amine 8b (1.00 g, 5.65 mmol), iodomethane (2.80 g, 19.77 mmol) and acetone (30 mL) were mixed. The mixture was stirred at 70 < 0 > C for 16 hours, cooled to room temperature and filtered. The solid was mixed with 10% sodium hydroxide (8 mL), stirred at 80 < 0 > C for 0.5 h and cooled to room temperature. The mixture was quenched with 250 mL of ice water, extracted with dichloromethane (50 mL x 2), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure to give the target product 8c 4- (Dimethoxymethyl) -N -methylpyrimidin-2-amine 8c (0.70 g, ) In 67% yield.

MS m / z (ESI): 184 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 8.37 (d, J = 4.8 Hz, 1H), 6.77 (d, J = 5.2 Hz, 1H), 5.18 (brs, 1H), 5.13 (s, 1H), 3.42 (s, 6H), 3.03 (d, J = 5.2 Hz, 3H).

Step 3

Phenyl (4- (dimethoxymethyl) pyrimidin-2-yl) (methyl) aminocarboxylate

The compound 4- (Dimethoxy-methyl) - N - methyl-pyrimidin-2-amine 8c (0.20 g, mmol 1.09), diphenyl carbonate (0.47 g, mmol 2.19), lithium hexamethyldisilazane Zaid (mL 1.5, 1.51 mmol , 1 M solution in tetrahydrofuran) and tetrahydrofuran (5 mL) were mixed and stirred at 0 ° C for 2 hours. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 50: 1) to give the target product phenyl (4- (dimethoxymethyl) pyrimidin-2-yl) (methyl) aminocarboxylate 8d , White solid) in 12% yield.

MS m / z (ESI): 304 [M + 1].

Step 4

Cyanopyrid-2-yl) -1- (4- (dimethoxymethyl) pyrimidin-2-yl)

Amino-4-chloronicotinonitrile (21 mg, 0.13 mmol), phenyl (4- (dimethoxymethyl) pyrimidin- Lithium hexamethyldisilazide (0.26 mL, 0.26 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 2 hours. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 50: 1) to give the target product 3- (4-chloro-5-cyanopyrid- Methyl) pyrimidin-2-yl) -1-methylurea 8e (25 mg, white solid) in 52% yield.

MS m / z (ESI): 363 & 365 [M + 1]

^{1 H NMR (400 MHz, CDCl} 3) δ 13.59 (s, 1H), 8.74 (d, J = 5.2 Hz, 1H), 8.56 (s, 1H), 8.55 (s, 1H), 7.30 (d, J = 5.2 Hz, 1 H), 5.34 (s, 1 H), 3.68 (s, 3 H), 3.51 (s, 6 H).

Step 5

Yl) -1- (4- (dimethoxymethyl) pyrimidin-2-yl) -1-methylurea

Yl) -1-methylurea 8e (18 mg, 0.05 mmol) was reacted with 3- (4-chloro-5-cyanopyrid- 2-methoxyethylamine (15 mg, 0.20 mmol), diisopropylethylamine (13 mg, 0.10 mmol) and N, N -dimethylacetamide (0.4 mL) were mixed and stirred at 70 ° C for 16 hours . The mixture was diluted with 10 mL of water, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 50: 1) to give the target product 3- (5-cyano-4 - ((2- methoxyethyl) amino) ) -1- (4- (dimethoxymethyl) pyrimidin-2-yl) -1-methylurea 8f (15 mg, yellow solid) in 75% yield.

MS m / z (ESI): 402 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.11 (s, 1H), 8.72 (d, J = 5.2 Hz, 1H), 8.23 (s, 1H), 7.65 (s, 1H), 7.25 (d, J = 2H), 3.51 (s, 1H), 5.31 (s, 1H), 5.30 (br s, 1H), 3.67-3.65 ), 3.44 (s, 3H).

Step 6

2-yl) -1- (4-formylpyrimidin-2-yl) -1-methylurea

Synthesis of 3- (5-cyano-4 - ((2- methoxyethyl) amino) pyrid-2-yl) -1- (4- (dimethoxymethyl) pyrimidin- Urea 8f (15 mg, 0.04 mmol), hydrochloric acid (0.8 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 3 hours. The mixture was quenched with saturated sodium carbonate solution, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 50: 1) to give the target product 3- (5-cyano-4 - ((2- methoxyethyl) amino) ) -1- (4-formylpyrimidin-2-yl) -1-methylurea 8 (6 mg, white solid) in 27% yield.

MS m / z (ESI): 356 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.88 (s, 1H), 10.06 (s, 1H), 8.95 (d, J = 4.8 Hz, 1H), 8.23 (s, 1H), 7.65 (s, 1H) , 7.52 (d, J = 4.8 Hz, 1 H), 5.35 (br s, 1H), 3.73 (s, 3H), 3.69-3.65 (m, 2H), 3.55-3.52 ).

Example 9

(6-formyl-5 - ((3-carbonylmorpholino) methyl) piperidine- Pyrid-2-yl) -1-methylurea

Step 1

Di-t-butyl (5-bromo-6-methylpyrid-2-yl)

(9.00 g, 50.00 mmol), 2-t-butyl 2-carbonate (27.00 g, 125 mmol) and N, N -dimethylpyridin- 0.31 g, 2.50 mmol) and tetrahydrofuran (300 mL) were mixed and stirred at room temperature for 16 hours. The mixture was quenched with 300 mL of water, extracted with ethyl acetate (200 mL x 2), and the organic phase was washed with saturated brine (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 100: 0 to 95: 5) to give the target product di-t-butyl (5-bromo-6-methylpyrid- Imidyl carbonate 9b (15.00 g, white solid) was obtained in 78% yield.

¹ H NMR (400 MHz, CDCl ₃ )? 7.80 (d, J = 8.4 Hz, 1H), 7.00 (d, J = 8.4 Hz, 1H), 2.61 (s, 3H), 1.46 (s,

Step 2

Di-t-butyl (5-bromo-6- (dibromomethyl) pyrid-2-yl) imidyl carbonate

(3.86 g, 10.00 mmol), 1-bromopyrrolidine-2,5-dione (4.45 g, 10.00 mmol) and di- 25.00 mmol), benzoyl peroxide anhydride (0.24 g, 1.00 mmol) and carbon tetrachloride (100 mL) were mixed and stirred at 90 ° C for 16 hours. The mixture was cooled to room temperature and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 94: 6) to give the target product di-t-butyl (5-bromo-6- (dibromomethyl) pyrid- ) Imidyl carbonate 9c (4.00 g, yellow solid) was obtained in 74% yield.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 1.50 (s, 18H).

Step 3

t-butyl (5-bromo-6- (dimethoxy) pyrid-2-yl) aminocarboxylate

Yl) imidyl carbonate 9c (5.00 g, 96.00 mmol), potassium hydroxide (2.23 g, 0.38 mol) and triethylamine And methanol (30 mL) were mixed and stirred at 70 占 폚 for 16 hours. The mixture was cooled to room temperature and eluted under reduced pressure. The residue was dissolved in 50 mL of water, extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 100: 0 to 12: 1) to give the target product t-butyl (5-bromo-6- (dimethoxy) pyrid- ) Aminocarboxylate 9d (0.50 g, yellow solid) in 16% yield.

MS m / z (ESI): 347 & 349 [M + 1].

Step 4

(5-bromo-6- (dimethoxy) pyrid-2-yl) (methyl) aminocarboxylate

Compound A mixture of t-butyl (5-bromo-6- (dimethoxy) pyrid-2-yl) aminocarboxylate 9d (1.20 g, 3.47 mmol), sodium hydride (0.18 g, 4.51 mmol, 60% ), Iodomethane (0.59 g, 4.16 mmol) and N, N -dimethylformamide (8 mL) were mixed and stirred at room temperature for 16 hours. The mixture was quenched with 30 mL of water, extracted with ethyl acetate (50 mL x 3) and the organic phase washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 100: 0 to 96: 4) to give the target product t-butyl (5-bromo-6- (dimethoxy) ) (Methyl) aminocarboxylate 9e (0.40 g, yellow oil) in 32% yield.

MS m / z (ESI): 361 & 363 [M + 1].

Step 5

Methyl-6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl) nicotinate

The compound 9e (0.45 g, 1.25 mmol), palladium acetate (28 mg, 0.13 mmol), 1, 5-dimethoxy- (0.14 g, 0.25 mmol), triethylamine (0.25 g, 2.50 mmol), methanol (3 mL) and N, N -dimethylformamide (20 mL) Was stirred at 100 < 0 > C for 16 hours in a carbon monoxide atmosphere (1 atm). The mixture was quenched with 100 mL of water, extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with saturated brine (50 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 96: 4) to give the target product methyl-6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl ) Nicotinate 9f (0.25 g, yellow oil) in 59% yield.

MS m / z (ESI): 341 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 3.91 (s, 3H), 3.52 (s, 6H), 3.41 (s, 3H), 1.53 (s, 9H).

Step 6

butyl (6- (dimethoxymethyl) -5- (hydroxymethyl) pyrid-2-yl) (methyl) aminocarboxylate

(0.30 g, 0.88 mmol) and sodium borohydride (0.67 g, 17.65 mmol) were added to a solution of methyl 6- (t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl) nicotinate 9f , Anhydrous calcium chloride (0.19 g, 1.77 mmol) and methanol (10 mL) were mixed and stirred at 65 ° C for 8 hours. The mixture was quenched with 10 mL of water, extracted with ethyl acetate (50 mL x 2), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure to give the target product t-butyl (6- (dimethoxymethyl) -5- (hydroxymethyl) pyrid- ) (Methyl) aminocarboxylate (0.20 g, white solid) in 73% yield.

MS m / z (ESI): 313 [M + 1].

Step 7

t-butyl (5- (bromomethyl) -6- (dimethoxymethylpyrid-2-yl) (methyl)

Compound 9 g (0.20 g, 0.64 mmol), phosphorus tribromide (0.21 g, 0.77 mmol) was added to a solution of t-butyl (6- (dimethoxymethyl) -5- (hydroxymethyl) pyrid- mmol) and dichloromethane (5 mL) were mixed and stirred at 0 ° C for 1 hour. The mixture was quenched with 10 mL of aqueous sodium bicarbonate solution, extracted with ethyl acetate (50 mL x 2), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 100: 0 to 93: 7) to give the target product t-butyl (5- (bromomethyl) -6- (dimethoxymethylpyrid- 2-yl) (methyl) aminocarboxylate 9h (0.15 g, colorless solid) in 63% yield.

MS m / z (ESI): 375 & 377 [M + 1].

Step 8

pyrid-2-yl) (methyl) aminocarboxylate < / RTI >

(70 mg, 0.19 mmol), morpholin-3-one (38 mg, 0.19 mmol) was added to a solution of t-butyl (5- (bromomethyl) -6- (dimethoxymethylpyrid- , 0.38 mmol), sodium hydride (19 mg, 0.47 mmol, 60% mineral oil mixture) and N, N -dimethylformamide (3 mL) were mixed and stirred at room temperature for 1 hour. (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2) The organic phase was dried over anhydrous sodium sulfate and filtered to remove the desiccant. Purification via a silica gel plate for purification (petroleum ether / ethyl acetate 1.5: 1) gave the target product t-butyl- (6- (2-methoxyethyl) -5 - ((3- carbonylmorpholine) methyl) Pyrid-2-yl) (methyl) aminocarboxylate 9i (70 mg, white solid) in 95% yield.

MS m / z (ESI): 396 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 7.63-7.61 (m, 2H), 5.22 (s, 1H), 4.91 (s, 2H), 4.26 (s, 2H), 3.82-3.81 (m, 2H), 3.45 (s, 6H), 3.40 (s, 3H), 3.27-3.26 (m, 2H), 1.52 (s, 9H).

Step 9

4- ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) methyl) morpholin-

(Methyl) aminocarboxylate 9i (70 mg, 0.18 mmol) was added to a solution of t-butyl- (6- (2-methoxyethyl) -5 - , Trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were mixed and stirred at room temperature for 6 hours. The mixture was alkalized using triethylamine and eluted under reduced pressure. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 4 - ((2- (dimethoxymethyl) -6- (methylamino) pyrid- Methyl) morpholin-3-one 9j (46 mg, colorless solid) in 86% yield.

MS m / z (ESI): 296 [M + 1].

Step 10

Phenyl- (6- (dimethoxymethyl) -5 - ((3-carbonylmorpholine) methyl) pyrid-2-yl) (methyl) aminocarboxylate

To a solution of 4 - ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) methyl) morpholin-3-one 9j (60 mg, 0.20 mmol), diphenyl carbonate 0.40 mmol), lithium hexamethyldisilazide (1.0 mL, 1.01 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (5 mL) were mixed and stirred at 0 ° C for 0.5 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 2: 1) to give the target product phenyl (6- (dimethoxymethyl) -5 - ((3- carbonylmorpholine) methyl) -2-yl) (methyl) aminocarboxylate 9k (45 mg, colorless oil) in 54% yield.

MS m / z (ESI): 416 [M + 1].

Step 11

2-yl) -1- (6- (dimethoxymethyl) -5 - ((3- carbonylmorpholine) methyl) pyrid- 1-methylurea

(Methyl) aminocarboxylate 9k (45 mg, 0.11 mmol), 6-amino-benzothiazol-2- (33 mL, 0.22 mmol), lithium hexamethyldisilazide (0.3 mL, 0.33 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (3 mL) were mixed and treated at room temperature with 1 Lt; / RTI > The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 3- (4-chloro-5-cyanopyrid- (3-carbonylmorpholine) methyl) pyrid-2-yl) -1-methylurea (40 mg, white solid) in 78% yield.

MS m / z (ESI): 475 & 477 [M + 1].

Step 12

5 - ((3-carbonylmorpholine) -1- (6- (dimethoxymethyl) Methyl) pyrid-2-yl) -1-methylurea

Yl) -1- (6- (dimethoxymethyl) -5 - ((3-carbonylmorpholine) methyl) pyrid- (20 mg, 0.04 mmol), 2-methoxyethylamine (13 mg, 0.17 mmol), diisopropylethylamine (11 mg, 0.08 mmol) and N, N -dimethylacetamide mL) were mixed and stirred at 50 DEG C for 16 hours. The mixture was quenched with 10 mL of water, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 3- (5-cyano-4 - ((2- methoxyethyl) amino) Yl) -1-methyl urea 9 mg (15 mg, white solid) was dissolved in 69% methanol to give the title compound as a white amorphous solid. 1H NMR (400 MHz, CDCl3)? . ≪ / RTI >

MS m / z (ESI): 514 [M + 1].

Step 13

(6-formyl-5 - ((3-carbonylmorpholine) methyl) piperidine-1-carboxylic acid ethyl ester was prepared from 3- (5-cyano- Yl) -1-methylurea

The compound 3- (5-cyano-4 - ((2- methoxyethyl) amino) pyrid-2-yl) -1- (6- (dimethoxymethyl) -5 - (15 mg, 0.03 mmol), hydrochloric acid (0.8 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were mixed, And the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated sodium carbonate solution, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was washed with ethyl acetate to give the target product 3- (5-cyano-4 - ((2-methoxyethyl) amino) pyrid- (3-carbonylmorpholine) methyl) pyrid-2-yl) -1-methylurea 9 (7 mg, white solid) in 52% yield.

MS m / z (ESI): 468 [M + 1] <

¹ H NMR (400 MHz, CDCl ₃ )? 12.99 (s, IH), 10.26 (s, IH), 8.17 (s, IH), 7.98 (d, J = 8.4 Hz, 2H), 3.61 (t, J = 4.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 1H), 5.31 (brs, J = 4.0 Hz, 2H), 3.53 (s, 3H), 3.51 (t, J = 4.4 Hz, 2H), 3.42 (s, 3H), 3.41 (d, J = 4.0 Hz, 2H).

Example 10

Preparation of 3- (5-cyano-4- (isopropylamino) pyrid-2-yl) -1- (6-formyl- Yl) -1-methylurea

Step 1

Di-t-butyl (5-bromo-6-methylpyrid-2-yl)

(50 g, 0.27 mol), 2-t-butyl 2-carbonate (145.16 g, 0.67 mol) and N, N -dimethylpyridin- 3.20 g, 27.00 mmol) and tetrahydrofuran (300 mL) were mixed and stirred at room temperature for 16 hours. The mixture was quenched with 300 mL of water, extracted with ethyl acetate (200 mL x 2), and the organic phase was washed with saturated brine (200 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was washed with petroleum ether to give the target product di-t-butyl (5-bromo-6-methylpyrid-2-yl) imidyl carbonate 10b (80.00 g, white solid) Respectively.

¹ H NMR (400 MHz, CDCl ₃ )? 7.80 (d, J = 8.4, 1H), 7.00 (d, J = 8.4 Hz, 1H), 2.61 (s, 3H), 1.46 (s,

Step 2

Di-t-butyl (5-bromo-6- (dibromomethyl) pyrid-2-yl) imidyl carbonate

Compound (10 g, 0.21 mol), 1-bromopyrrolidine-2,5-dione (110.00 g, 0.63 mol), benzoyl peroxide anhydride (0.24 g, 0.06 mol) and carbon tetrachloride (600 mL) were mixed and stirred at 90 DEG C for 16 hours. The mixture was cooled to room temperature and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 94: 6) to give the target product di-t-butyl (5-bromo-6- (dibromomethyl) pyrid- ) Imidyl carbonate 10c (90.00 g, yellow solid) was obtained in 80% yield.

^{1 H NMR (400 MHz, CDCl} 3) δ 7.82 (d, J = 8.0 Hz, 1H), 7.26 (d, J = 8.0 Hz, 1H), 7.08 (s, 1H), 1.50 (s, 18H).

Step 3

5-Bromo-6- (dimethoxymethyl) pyridin-2-amine

(90.00 g, 0.17 mol), potassium hydroxide (38.52 g, 0.66 mol) and di-t-butyl (5-bromo-6- (dibromomethyl) pyrid- And methanol (300 mL) were mixed and stirred at 70 占 폚 for 72 hours. The mixture was cooled to room temperature and eluted under reduced pressure. The residue was dissolved in 500 mL of water, extracted with ethyl acetate (500 mL x 3) and the organic phase washed with saturated brine (500 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 100: 0-12: 1) to give the target product 5-bromo-6- (dimethoxymethyl) pyridin- , Yellow solid) in 54% yield.

MS m / z (ESI): 247 & 249 [M + l]

^{1 H NMR (400 MHz, CDCl} 3) δ 7.54 (d, J = 8.4 Hz, 1H), 6.38 (d, J = 8.4 Hz, 1H), 5.61 (s, 1H), 4.63 (brs, 2H), 3.48 (s, 6 H).

Step 4

5-Bromo-6- (dimethoxymethyl) -N -methylpyridin-2-amine

A solution of 10d (22.00 g, 89.43 mmol), sodium methoxide (24.15 g, 447 mmol), paraformaldehyde (10.74 g, 358 mmol) and methanol (300 mL) were mixed and stirred at 80 < 0 > C for 16 hours. The mixture was cooled and sodium borohydride (13.59 g, 358 mmol) was added thereto and stirred at 80 ° C for 1 hour. The mixture was quenched with 300 mL of water, extracted with ethyl acetate (500 mL x 3), and the organic phase was washed with saturated brine (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified by silica gel column chromatography (petroleum ether / ethyl acetate 100: 0 to 96: 4) to give via the target product 5-bromo-6- (dimethoxymethyl) - N - methyl-2-amine 10e (8.20 g, yellow solid) in 34% yield.

MS m / z (ESI): 261 & 263 [M + 1]

^{1 H NMR (400 MHz, CDCl} 3) δ 7.58 (d, J = 8.8 Hz, 1H), 6.27 (d, J = 8.8 Hz, 1H), 5.59 (s, 1H), 4.87 (brs, 1H), 3.48 (s, 6H), 2.87 (d, J = 5.2 Hz, 3H).

Step 5

Methyl-2- (dimethoxymethyl) -6- (methylamino) nicotinate

Compound 5-bromo-6- (dimethoxymethyl) - N - methyl-2-amine 10e (8.00 g, 30.77 mmol) , palladium acetate (0.69 g, 3.08 mmol), 1,1- bis (diphenylphosphino (3.41 g, 6.16 mmol), triethylamine (6.22 g, 61.54 mmol), methanol (30 mL) and N, N -dimethylformamide (400 mL) Lt; 0 > C. The mixture was quenched with 700 mL of water, extracted with ethyl acetate (500 mL x 3), and the organic phase was washed with saturated brine (500 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 94: 6) to give the target product methyl-2- (dimethoxymethyl) -6- (methylamino) nicotinate 10f (2.30 g, Solid) in 30% yield.

MS m / z (ESI): 241 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 8.05 (d, J = 8.8 Hz, 1H), 6.32 (d, J = 8.8 Hz, 1H), 6.24 (s, 1H), 5.30 (brs, 1H), 3.86 (s, 3H), 3.51 (s, 6H), 2.95 (d, J = 5.2 Hz, 3H).

Step 6

Methyl-6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl) nicotinate

(2.00 g, 8.33 mmol), 2-t-butyl 2-carbonate (3.60 g, 16.67 mol), N, N -dimethyl Pyridin-4-amine (0.10 g, 0.83 mmol) and tetrahydrofuran (50 mL) were mixed and stirred at room temperature for 2 hours. The mixture was quenched with 100 mL of water, extracted with ethyl acetate (100 mL x 3), and the organic phase was washed with saturated brine (100 mL x 3). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 94: 6) to give the target product methyl-6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl ) Nicotinate (2.20 g, yellow oil) in 78% yield.

MS m / z (ESI): 341 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 8.07 (d, J = 8.8 Hz, 1H), 7.84 (d, J = 8.8 Hz, 1H), 6.08 (s, 1H), 3.91 (s, 3H), 3.52 (s, 6H), 3.49 (s, 3H), 1.53 (s, 9H).

Step 7

butyl (6- (dimethoxymethyl) -5- (hydroxymethyl) pyrid-2-yl) (methyl) aminocarboxylate

(2.20 g, 6.47 mmol) and sodium borohydride (2.46 g, 60.47 mmol) in methylene-6 - ((t-butoxycarbonyl) , Anhydrous calcium chloride (1.42 g, 12.90 mmol) and methanol (20 mL) were mixed and stirred at 65 ° C for 2 hours. The mixture was quenched with 100 mL of water, extracted with ethyl acetate (100 mL x 2), and the organic phase was washed with saturated brine (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure to give the target product t-butyl- (6- (dimethoxymethyl) -5- (hydroxymethyl) pyrid- 2- Yl) (methyl) aminocarboxylate 10h (1.70 g, white solid) in 84% yield.

MS m / z (ESI): 313 [M + 1].

Step 8

t-butyl (5- (bromomethyl) -6- (dimethoxymethylpyrid-2-yl) (methyl)

10 g (1.70 g, 5.45 mmol) of t-butyl (6- (dimethoxymethyl) -5- (hydroxymethyl) pyrid- mmol) and dichloromethane (50 mL) were mixed and stirred at 0 ° C for 0.5 hour. The mixture was quenched with 10 mL of aqueous sodium bicarbonate solution, extracted with ethyl acetate (100 mL x 2), and the organic phase washed with saturated brine (100 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified via silica gel column chromatography (petroleum ether / ethyl acetate 100: 0 to 94: 6) to give the target product t-butyl- (5- (bromomethyl) -6- (dimethoxymethylpyrid -2-yl) (methyl) aminocarboxylate 10i (0.80 g, colorless solid) in 40% yield.

MS m / z (ESI): 375 & 377 [M + 1].

Step 9

pyrid-2-yl) (methyl) aminocarboxylate < / RTI >

(0.28 g, 0.76 mmol), morpholin-3-one (0.15 g, 0.76 mmol) was added to a solution of t- butyl- (5- (bromomethyl) -6- (dimethoxymethylpyrid- g, 1.52 mmol), sodium hydride (76 mg, 1.88 mmol, 60% mineral oil mixture) and N, N -dimethylformamide (10 mL) were stirred at room temperature for 1 hour. The organic phase was washed with saturated brine (50 mL x 2), dried over anhydrous sodium sulfate and filtered to remove the drying agent. Was purified via silica gel column chromatography (petroleum ether / ethyl acetate = 100: 0 to 7: 3) to give the target product t-butyl- (6- (2- methoxyethyl) -5 - Methyl) pyrid-2-yl) (methyl) aminocarboxylate 10j (0.27 g, white solid) in 91% yield.

MS m / z (ESI): 396 [M + 1].

Step 10

4- ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) methyl) morpholin-

(Methyl) aminocarboxylate 10j (0.27 g, 0.18 mmol) was added to a solution of t-butyl- (6- (2-methoxyethyl) -5 - , Trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were mixed and stirred at room temperature for 6 hours. The mixture was eluted under reduced pressure to give the target product 4 - ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) methyl) morpholin-3-one trifluoroacetate 10k , Yellow solid).

MS m / z (ESI): 296 [M + 1].

Step 11

Phenyl- (6- (dimethoxymethyl) -5 - ((3-carbonylmorpholine) methyl) pyrid-2-yl) (methyl) aminocarboxylate

3-yl) methyl) morpholin-3-one trifluoroacetate 10k (0.25 g, 0.60 mmol), diphenyl carbonate (0.26 g, 1.20 mmol), lithium hexamethyldisilazide (1.8 mL, 1.80 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (8 mL) were mixed and stirred at 0 ° C for 0.5 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (50 mL x 2), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 2: 1) to give the target product phenyl- (6- (dimethoxymethyl) -5 - ((3- carbonylmorpholine) methyl) Yl) (methyl) aminocarboxylate (0.13 g, colorless oil) in 51% yield.

MS m / z (ESI): 416 [M + 1].

Step 12

2-yl) -1- (6- (dimethoxymethyl) -5 - ((3- carbonylmorpholine) methyl) pyrid- 1-methylurea

(45 mg, 0.11 mmol), 6-amino-2-pyrrolidin-1-ylmethyl) amino] carboxylate was added to a solution of phenyl (6- (dimethoxymethyl) -5- (3- carbonylmorpholine) methyl) (33 mL, 0.22 mmol), lithium hexamethyldisilazide (0.3 mL, 0.33 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (3 mL) were mixed and treated at room temperature with 1 Lt; / RTI > The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 3- (4-chloro-5-cyanopyrid- (3-carbonylmorpholine) methyl) pyrid-2-yl) -1-methylurea (38 mg, white solid) in 74% yield.

MS m / z (ESI): 475 & 477 [M + 1].

Step 13

5- ((3-carbonylmorpholino) methyl) pyrid-2-yl) -1- (6- (dimethoxymethyl) Yl) -1-methylurea

Yl) -1- (6- (dimethoxymethyl) -5 - ((3-carbonylmorpholine) methyl) pyrid- (10 mg, 0.02 mmol), isopropylamine (5 mg, 0.08 mmol), diisopropylethylamine (6 mg, 0.04 mmol) and N, N -dimethylacetamide Mixed and stirred at 50 < 0 > C for 16 hours. This mixture was quenched with 10 mL of water, extracted with dichloromethane (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 3- (5-cyano-4- (isopropylamino) pyrid- Yl) -1-methylurea 10n (5 mg, white solid) was obtained in a yield of 48%. MS (m / z) Respectively.

MS m / z (ESI): 498 [M + 1].

Step 14

Preparation of 3- (5-cyano-4- (isopropylamino) pyrid-2-yl) -1- (6-formyl- Yl) -1-methylurea

Compound 3- (5-cyano-4- (isopropylamino) pyrid-2-yl) -1- (6- (dimethoxymethyl) -5 - ((3- carbonylmorpholino) (5 mg, 0.01 mmol), hydrochloric acid (0.8 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were mixed, and the mixture was stirred at room temperature for 1 hour Lt; / RTI > This mixture was quenched with saturated sodium carbonate solution, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 3- (5-cyano-4- (isopropylamino) pyrid- Yl) -1-methylurea 10 (3 mg, white solid) in 66% yield, MS (ISP): m /

MS m / z (ESI): 452 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 12.95 (s, 1H), 10.26 (s, 1H), 8.15 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H), 7.56 (s, 1H) , 7.30 (d, J = 8.8 Hz, 1H), 5.13 (s, 2H), 4.78-4.76 (m, 1H), 4.26 (s, 2H), 3.89 (t, J = 4.4 Hz, 2H), 3.88 ( 2H), 1.31 (d, J = 4.8 Hz, 6H), 3.53 (s, 3H), 3.43 (t, J = 4.4 Hz, 2H).

Example 11

Yl) -3- (6-formyl-5 - ((3-carbonylmorpholine) methyl) pyrid-

(3- (5-cyano-4 - ((2-methoxyethyl) amino) Yl) -3- (6-formyl-5 - ((3 (methylsulfonyl) -Carbonylmorpholine) methyl) pyrid-2-yl) urea. Example 11 was synthesized with reference to the operating sequence of Example 9.

MS m / z (ESI): 429 & 431 [M + 1]

^{1 H NMR (400 MHz, CDCl} 3) δ 13.60 (s, 1H), 10.26 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 8.01 (d, J = 8.8 Hz, 1H) , 7.28 (d, J = 8.8 Hz, 1H), 5.13 (s, 2H), 4.26 (s, 2H), 3.91 (t, J = 3.2 Hz, 2H), 3.55 (s, 3H), 3.44 (t, J = 3.2 Hz, 2H).

Example 12

3- (6-formyl-5 - ((3-carbonylmorpholino) methyl) pyrido [ Yl) urea

Step 1

6-Amino-4- (2-methoxyethoxy) nicotinonitrile

(60 mg, 0.39 mmol), 2-methoxyethanol (60 mg, 0.78 mmol), sodium hydride (34 mg, 0.86 mmol, 60% mineral oil mixture) and 6-amino-4-chloronicotinonitrile 12a N -methylpyrrolidone (1.5 mL) were mixed and stirred at 70 占 폚 for 16 hours. The mixture was cooled to room temperature, the mixture was quenched with 20 mL of water, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate = 1: 1) to give the target product 6-amino-4- (2-methoxyethoxy) nicotinonitrile 12b (30 mg, ) In 40% yield.

MS m / z (ESI): 194 [M + 1].

Step 2

5- ((3-carbonylmorpholine) methyl) -1- (6- (dimethoxymethyl) -5- (2- methoxyethoxy) pyrid- Pyrid-2-yl) -1-methylurea

Referring to the operating steps in Example 11, Step 11, but replacing 6-amino-4-chloronicotinonitrile with 6-amino-4- (2-methoxyethoxy) nicotinonitrile, To give the target product 3- (5-cyano-4- (2-methoxyethoxy) pyrid-2-yl) -1- (6- (dimethoxymethyl) Methyl) pyrid-2-yl) -1-methylurea 12c (8 mg, white solid) in 70% yield.

MS m / z (ESI): 515 [M + 1].

Step 3

Preparation of 3- (5-cyano-4- (2-methoxyethoxy) pyrid-2-yl) 2-yl) -1-methylurea

5 - ((3-carbonylmorpholine) -1- (6- (dimethoxymethyl) Methyl) pyrid-2-yl) -1-methylurea was converted to 3- (5-cyano-4- (2- methoxyethoxy) ), Was prepared in accordance with the general method of example 12, but using in step 13 the compound was prepared following the procedure in step 13 of Example 9, except substituting 2- (3-carbonylmorpholine) methyl) pyrid-2-yl) Synthesis was carried out to obtain the target product 3- (5-cyano-4-isopropoxypyrid-2-yl) -1- (6-formylpyrid- Solid) in 82% yield.

MS m / z (ESI): 469 [M + 1] <

¹ H NMR (400 MHz, CDCl ₃ )? 13.34 (s, IH), 10.27 (s, IH), 8.36 (s, IH), 8.00 (d, J = 8.8 Hz, , 7.18 (d, J = 7.6 Hz, 1H), 5.13 (s, 2H), 4.35 (s, 2H), 4.26 (d, J = 3.2 Hz, 2H), 3.90 (t, J = 3.2 Hz, 2H) , 3.83 (t, J = 4.0 Hz, 2H), 3.54 (s, 3H), 3.38 (s, 3H), 3.43 (t, J = 4.0 Hz, 2H).

Example 13

Yl) -3- (6-formyl-5 - ((3-carbonylmorpholine) methyl) pyrid-2-yl) urea

Example 13 was synthesized with reference to the operating steps of Example 12 except that in Step 1, 2-methoxyethanol was replaced with isopropanol.

MS m / z (ESI): 453 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.26 (s, 1H), 10.27 (s, 1H), 8.34 (s, 1H), 8.00 (d, J = 8.8 Hz, 1H), 7.93 (s, 1H) , 7.32 (d, J = 8.8 Hz, 1H), 5.13 (s, 2H), 4.87-4.85 (m, 1H), 4.26 (s, 2H), 3.54 (s, 3H), 3.47 (t, J = 4.4 Hz, 2H), 3.43 (t, J = 4.4 Hz, 2H), 1.45 (d, J = 3.2 Hz, 6H).

Example 14

( R ) -3- (5-cyano-4 - ((1-methoxyprop-2-yl) oxo) pyrid- -Carbonylmorpholino) methyl) pyrid-2-yl) -1-methylurea

Example 14 was synthesized with reference to the operating steps of Example 12, except that in Step 1, 2-methoxyethanol was replaced with ( R ) -1-methoxypropan-2-ol.

MS m / z (ESI): 483 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.27 (s, 1H), 10.26 (s, 1H), 8.34 (s, 1H), 7.99 (s, 1H), 7.98 (d, J = 8.8 Hz, 1H) , 7.32 (d, J = 8.8 Hz, 1H), 5.13 (s, 2H), 4.87-4.86 (m, 1H), 4.26 (s, 2H), 3.90 (t, J = 4.4 Hz, 2H), 3.64- 3.60 (m, 1H), 3.56-3.55 (m, 1H), 3.54 (s, 3H), 3.49 (t, J = 4.4 Hz, 2H), 3.43 (s, 3H), 1.43 (d, J = 3.2 Hz , 3H).

Example 15

(6-formyl-5 - ((4-methyl-2-carbonylpiperazin-1-ylmethyl) Yl) methyl) pyrid-2-yl) -1-methylurea hydrochloride

Step 1

methyl) pyrid-2-yl) (methyl) aminocarboxylate < RTI ID = 0.0 >

The compound 15a (70 mg, 0.19 mmol), 4- methylpiperazin-2-yl (methyl) amino carboxylate 15a (43 mg, 0.38 mmol), sodium hydride (19 mg, 0.47 mmol, 60% mineral oil mixture) and N, N -dimethylformamide (3 mL) were mixed and stirred at room temperature for 1 hour. The mixture was quenched with water, extracted with dichloromethane (20 mL x 3) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1.5: 1) to give the target product t-butyl- (6- (dimethoxymethyl) -5 - Yl) methyl) pyrid-2-yl) (methyl) aminocarboxylate 15b (60 mg, colorless solid) in 83% yield.

MS m / z (ESI): 409 [M + 1].

Step 2

1 - ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) methyl) -4-methylpiperazin-

Synthesis of t-butyl (6- (dimethoxymethyl) -5 - ((4-methyl-2-carbonylpiperazin-1-yl) methyl) pyrid- 60 mg, 0.15 mmol), trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were mixed and stirred at room temperature for 6 hours. The mixture was eluted under reduced pressure to give the target product 1 - ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3- yl) methyl) -4-methylpiperazin-2-one trifluoroacetate Salt 15c (60 mg, pale yellow solid) as a crude product.

MS m / z (ESI): 309 [M + 1].

Step 3

Phenyl) - (6- (dimethoxymethyl) -5 - ((4-methyl-2- carbonylpiperazin- 1 -yl) methyl) pyrid-

Compound 1 - ((2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) methyl) -4-methylpiperazin-2-one trifluoroacetate salt 15c (60 mg, 0.14 mmol ), Diphenyl carbonate (60 mg, 0.28 mmol), lithium hexamethyldisilazide (0.56 mL, 0.56 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (5 mL) Lt; / RTI > The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 30: 1) to give the target product phenyl- (6- (dimethoxymethyl) -5 - ((4-methyl-2-carbonylpiperazine- Yl) methyl) pyrid-2-yl) (methyl) aminocarboxylate 15d (30 mg, colorless solid) in 36% yield.

MS m / z (ESI): 429 [M + 1].

Step 4

5- ((4-methyl-2-carbonylpiperazin-1-yl) methyl) -1- (6- (dimethylamino) Pyrid-2-yl) -1-methylurea

Pyrid-2-yl) (methyl) aminocarboxylate 15d (30 mg) was added to a solution of phenyl (6- (dimethoxymethyl) , 0.07 mmol), 6-amino-4-chloronicotinonitrile (21 mg, 0.14 mmol), lithium hexamethyldisilazide (0.21 mL, 0.21 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran mL) were mixed and stirred at room temperature for 1 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 30: 1) to give the target product 3- (4-chloro-5-cyanopyrid-2-yl) -1- (6- (dimethoxy Yl) -1-methylurea 15e (17 mg, white solid) was obtained in a yield of 50%. MS: m / e = .

MS m / z (ESI): 488 & 490 [M + 1]

^{1 H NMR (400 MHz, CDCl} 3) δ 13.82 (s, 1H), 8.52 (s, 1H), 8.46 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.04 (d, J = 8.4 Hz, 1H), 5.47 ( s, 1H), 4.86 (s, 2H), 3.47 (s, 6H), 3.46 (s, 3H), 3.27 (s, 2H), 3.20 (t, J = 4.4 Hz, 2H), 2.62 (t, J = 4.4 Hz, 2H), 2.35 (s, 3H).

Step 5

5 - ((4-methyl-2-carbo < / RTI > Yl) methyl) pyrid-2-yl) -1-methylurea

Compound 3- (4-chloro-5-cyanopyridazin-2-yl) -1- (6- (dimethoxymethyl) (4 mg, 0.008 mmol), 2-methoxyethylamine (2 mg, 0.024 mmol), diisopropylethylamine (2 mg, 0.016 mmol) and N , N -dimethylacetamide (0.4 mL) were mixed and stirred at 50 ° C for 16 hours. The mixture was quenched with 10 mL of water, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 25: 1) to give the target product 3- (5-cyano-4 - ((2- methoxyethyl) amino) Yl) -1-methylurea 15f (2 mg) was added to a solution of 2-amino-2- , White solid) in 46% yield.

MS m / z (ESI): 527 [M + 1].

Step 6

(6-formyl-5 - ((4-methyl-2-carbonylpiperazin-1-ylmethyl) Yl) methyl) pyrid-2-yl) -1-methylurea hydrochloride

The compound 3- (5-cyano-4 - ((2-methoxyethyl) amino) pyrid- Yl) -1-methylurea 15f (2 mg, 0.004 mmol), hydrochloric acid (0.8 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 1 hour. The mixture was eluted under reduced pressure to give the target product 3- (5-cyano-4 - ((2-methoxyethyl) amino) pyrid- Methyl) pyrid-2-yl) -1-methylurea hydrochloride 15 (1.5 mg, white solid) in 67% yield.

MS m / z (ESI): 481 [M + 1] <

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.40 (s, 1H), 7.98 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 8.4 Hz, 1H), 6.94 (s, 1H), 6.92 (s, 1H), 4.91 (s, 2H), 3.75 (t, J = 6.8 Hz, 2H), 3.69-3.60 (m, 2H), 3.45-3.42 (m, 4H), 3.37 (s, 3H) , 3.36 (s, 3H), 3.26-3.21 (m, 2H), 3.03 (s, 3H).

Example 16

5- ((4-methyl-2-carbonylpiperazin-1-yl) -1H-pyrazol- Methyl) pyrid-2-yl) -1-methylurea

Example 16 was synthesized with reference to the operating steps of Example 15, but replacing 2-methoxyethylamine with isopropylamine in step 5. [

MS m / z (ESI): 465 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 12.95 (s, 1H), 10.25 (s, 1H), 8.16 (s, 1H), 7.95 (d, J = 8.0 Hz, 1H), 7.56 (s, 1H) , 7.28 (d, J = 8.0 Hz, IH), 5.10 (s, 2H), 4.76 (brs, IH), 3.89-3.87 (m, 3.20 (t, J = 4.0 Hz , 2H), 2.66 (t, J = 4.0 Hz, 2H), 2.35 (s, 3H), 1.32 (d, J = 5.2 Hz, 6H).

Example 17

5 - ((4-methyl-2-carbonylpiperazin-1-yl) methyl) pyrid- 2-yl) -1-methylurea

(6- (dimethoxymethyl) -5 - ((4-methyl-pyridin-2-yl) Yl) -1- (6- (4-chloro-5-cyanopyridazin-2-yl) The title compound was prepared following the same procedure as described in the preparation of Example 15, but using in step (5), except substituting (4-methyl-2-pyridin-2-ylmethyl) , Example 17 was synthesized.

MS m / z (ESI): 442 & 444 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.59 (s, 1H), 10.26 (s, 1H), 8.51 (s, 1H), 8.46 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H) , 7.31 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 3.54 (s, 3H), 3.38 (s, 2H), 3.20 (t, J = 4.4 Hz, 2H), 2.68 (t, J = 4.4 Hz, 2H), 2.36 (s, 3H).

Example 18

(R) -3- (5- cyano-4 - ((1-methoxy-prop-2-yl) oxo) pyrid-2-yl) -1- (6-formyl-5 - ((4 Methyl-2-carbonylpiperazin-1-yl) methyl) pyrid-2-yl) -1-methylurea

Step 1

( R ) -6-amino-4 - ((1-methoxyprop-2-yl) oxo) nicotinonitrile

(60 mg, 0.39 mmol), ( R ) -1-methoxypropan-2-ol (70 mg, 0.78 mmol) and sodium hydride (34 mg, 0.86 mmol , 60% mineral oil mixture) and N -methyl pyrrolidone (1.5 mL) were mixed and stirred at 70 ° C for 16 hours. The mixture was cooled to room temperature, the mixture was quenched with 20 mL of water, extracted with ethyl acetate (20 mL x 2) and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified via a silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product ( R ) -6-amino-4 - ((1-methoxyprop- Nicotinonitrile 18b (17 mg, white solid) in 21% yield.

MS m / z (ESI): 208 [M + 1] <

¹ H NMR (400 MHz, CDCl ₃ )? 8.17 (s, IH), 6.00 (s, IH), 4.94 (brs, 2H), 4.63-4.60 3.54-3.51 (m, 1 H), 3.41 (s, 3 H), 1.38 - 1.36 (m, 3 H).

Step 2

( R ) -3- (5-cyano-4 - ((1-methoxyprop-2-yl) oxo) pyrid- ((4-methyl-2-carbonylpiperazin-1-yl) methyl) pyrid-2-yl)

Pyridin-2-yl) (methyl) aminocarboxylate (10 mg, 0.20 mmol) was added to a solution of phenyl- (6- (dimethoxymethyl) 0.02 mmol), lithium hexamethyldisilazide (0.06 mL, 0.04 mmol), ( R ) -6-amino- , 0.06 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 1 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with dichloromethane (20 mL x 3), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 30: 1) to give the target product ( R ) -3- (5-cyano- Yl) methyl) pyrid-2-yl) -1- (6- (dimethoxymethyl) -1-methylurea 18c (6 mg, white solid) in 47% yield.

MS m / z (ESI): 542 [M + 1].

Step 3

(R) -3- (5- cyano-4 - ((1-methoxy-prop-2-yl) oxo) pyrid-2-yl) -1- (6-formyl-5 - ((4 Methyl-2-carbonylpiperazin-1-yl) methyl) pyrid-2-yl) -1-methylurea

( R ) -3- (5-cyano-4 - ((1-methoxyprop-2-yl) oxo) pyrid- Yl) -1-methylurea 18c (6 mg, 0.01 mmol), hydrochloric acid (0.8 mL, 37%), Water (1 mL) and tetrahydrofuran (2 mL) were mixed and stirred at room temperature for 1 hour. The mixture was quenched with saturated sodium carbonate solution, extracted with dichloromethane (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (dichloromethane / methanol 25: 1) to give the target product ( R ) -3- (5-cyano- Yl) -1- (6-formyl-5 - ((4-methyl-2- carbonylpiperazin- 1- yl) methyl) pyrid- Methylurea 18 (4 mg, white solid) in 73% yield.

MS m / z (ESI): 496 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.28 (s, 1H), 10.27 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 7.6 Hz, 1H) 2H), 3.57 (s, 3H), 3.49 (s, 3H), 7.27 (d, J = 7.6 Hz, ), 3.43 (s, 2H), 3.20 (t, J = 4.4 Hz, 2H), 2.67 (t, J = 4.4 Hz, 2H), 2.36 (s, 3H), 1.42-1.40 (m, 3H).

Example 19

Methyl-2- (4-methyl-2-carbonylpiperazin-1-yl) methyl) Pyrid-2-yl) -1-methylurea

Example 19 was synthesized with reference to the operating steps of Example 18, except for ( R ) -1-methoxypropan-2-ol in Step 1 was replaced with isopropanol.

MS m / z (ESI): 466 [M + 1] <

¹ H NMR (400 MHz, CDCl ₃ )? 13.28 (s, IH), 10.26 (s, IH), 8.34 (s, IH), 7.96 (d, J = 8.4 Hz, , 7.26 (d, J = 8.4 Hz, 1H), 5.10 (s, 2H), 4.85-4.83 (m, 1H), 3.49 (s, 3H), 3.38 (s, 2H), 3.21 (t, J = 4.4 Hz, 2H), 2.69 (t, J = 4.4 Hz, 2H), 2.36 (s, 3H), 1.45 (d, J = 4.0 Hz, 6H).

Example 20

Preparation of 3- (5-cyano-4- (2-methoxyethoxy) pyrid-2-yl) Yl) methyl) pyrid-2-yl) -1-methylurea

Example 20 was synthesized with reference to the operating steps of Example 18, except that ( R ) -l-methoxypropan-2-ol was replaced with 2-methoxyethanol in Step 1.

MS m / z (ESI): 482 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.34 (s, 1H), 10.27 (s, 1H), 8.36 (s, 1H), 7.96 (s, 1H), 7.95 (d, J = 8.4 Hz, 1H) , 7.31 (d, J = 8.4 Hz, 1H), 5.11 (s, 2H), 4.35 (t, J = 4.0 Hz, 2H), 3.83 (t, J = 4.0 Hz, 2H), 3.53 (s, 3H) , 3.48 (s, 3H), 3.37 (s, 2H), 3.20 (t, J = 4.4 Hz, 2H), 2.67 (t, J = 4.4 Hz,

Example 21

2-yl) -1- (6-formyl-5- (hydroxymethyl) pyrid-2-yl) -1-methylurea

Step 1

5 - (((t-butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl) -N -methylpyridin-

(60 mg, 0.28 mmol), t-butyldimethylsilyl chloride (64 mg, 0.42 mmol), N -ethyl (4-methylphenyl) - N - isopropyl-propan-2-amine (72 mg, 0.56 mmol), N, N - dimethyl-4-amine (7 mg, 0.06 mmol) and dichloro-methane mixture (4 mL) and, at room temperature for 6 hours Lt; / RTI > The mixture was quenched with 20 mL of water, extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate = 15: 1) to give the target product 5 - (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl) N -Methylpyridin-2-amine 21b (60 mg, colorless oil) in 65% yield.

MS m / z (ESI): 327 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 7.57 (d, J = 8.0 Hz, 1H), 6.28 (d, J = 8.0 Hz, 1H), 5.21 (s, 1H), 4.69 (s, 2H), 4.57 (br s, 1H), 3.32 (s, 6H), 2.80 (s, 3H), 0.84 (s, 9H), 0.08 (s, 6H).

Step 2

Phenyl) - (5 - ((t-butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl) pyrid-

Compound 5 - (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxy-methyl) - N - methyl-2-amine 21b (22 mg, 0.07 mmol) , diphenyl carbonate (15 mg, 0.14 mmol), lithium hexamethyldisilazide (0.21 mL, 0.21 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (3 mL) were mixed and stirred at 0 ° C for 0.5 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 5: 1) to give the target product phenyl- (5 - (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl ) Pyrid-2-yl) (methyl) aminocarboxylate 21c (18 mg, white solid) in 60% yield.

MS m / z (ESI): 447 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 7.86 (d, J = 8.4 Hz, 1H), 7.58 (d, J = 7.2 Hz, 1H), 7.27-7.25 (m, 2H), 7.15-7.04 (m, 3H), 3.34 (s, 6H), 0.85 (s, 9H), 0.08 (s, 6H).

Step 3

Yl) -3- (4-chloro-5-cyanopyrid-2-yl) -1- (5 - ((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl) ) -1-methylurea

(Methyl) aminocarboxylate 21c (18 mg, 0.04 mmol), 6 (dimethylamino) pyrid-2-yl) (12 mg, 0.08 mmol), lithium hexamethyldisilazide (0.12 mL, 0.12 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (2 mL) were mixed, And the mixture was stirred at room temperature for 1 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 3: 1) to give the target product 1- (5 - (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl ) Pyrid-2-yl) -3- (4-chloro-5-cyanopyrid-2-yl) -1-methylurea 21d (16 mg, white solid) in 79% yield.

MS m / z (ESI): 506 & 508 [M + 1]

^{1 H NMR (400 MHz, CDCl} 3) δ 13.78 (s, 1H), 8.40 (s, 1H), 8.34 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H), 6.97 (d, J = 8.8 Hz, 1H), 5.35 (s, 1H), 4.78 (s, 2H), 3.37 (s, 3H), 3.33 (s, 6H), 0.83 (s, 9H)

Step 4

3- (5-cyano-4 - ((2-methoxyphenyl) -5-methyl- Ethyl) amino) pyrid-2-yl) -1-methylurea

3- (4-Chloro-5-cyanopyrid-2-yl) -3- (4-chloro-5-cyanopyridyl) (10 mg, 0.02 mmol), 2-methoxyethylamine (3 mg, 0.06 mmol), diisopropylethylamine (5 mg, 0.06 mmol) and N, N -dimethylacetamide (0.4 mL) were mixed and stirred at 50 < 0 > C for 16 hours. The mixture was diluted with 10 mL of water, extracted with ethyl acetate (20 mL x 2), and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 3: 1) to give the target product 1- (5 - (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl Yl) -1-methylurea 21e (9 mg, white solid) was converted to the title compound, MS: m / e = 76%. ≪ / RTI >

MS m / z (ESI): 545 [M + 1].

Step 5

2-yl) -1- (6-formyl-5- (hydroxymethyl) pyrid-2-yl) -1-methylurea

3- (5-cyano-4 - ((2-methylpiperazin-1-ylmethyl) Methylurea 21e (9 mg, 0.02 mmol), hydrochloric acid (0.8 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were mixed And the mixture was stirred at room temperature for 1 hour. The mixture was quenched with saturated sodium carbonate solution, extracted with ethyl acetate (20 mL x 2), and the organic phase was washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified via silica gel plate for purification (petroleum ether / ethyl acetate 1: 1) to give the target product 1- (5 - (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl Yl) -l-methylurea 21 (3 mg, white solid) was reacted with (2-methoxyethyl) 47%. ≪ / RTI >

MS m / z (ESI): 385 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ major product (major) (21 '): 12.60 (s, 1H), 8.08 (s, 1H), 7.70 (d, J = 7.6 Hz, 1H), 7.58 (s (M, 1H), 7.07 (d, J = 7.6 Hz, IH), 6.53 (s, IH), 5.31 3.61 (m, 2H), 3.51-3.50 (m, 2H), 3.49 (s, 3H), 3.41 (s, 3H). By-product (Minor) (21): 12.94 (s, 1H), 10.25 (s, 1H), 8.17 (s, 1H), 8.06 (d, J = 8.4 Hz, 1H), 7.57 (s, 1H), 7.27 (d, J = 8.4 Hz, IH), 6.53 (s, IH), 5.31 (s, IH), 5.25-5.23 ), 3.51-3.50 (m, 2H), 3.49 (s, 3H), 3.41 (s, 3H).

Example 22

(3-chloro-5-cyanopyrid-2-yl) -1- (6-formyl-5- (hydroxymethyl) pyrid-

(5-cyano-4 - ((2-methoxyethyl) amino) pyrid- Yl) -3- (4-chloro-pyridin-2-yl) -methylurea was prepared in accordance with the general method of example 1 from 1- (5- (((t- butyldimethylsilyl) oxo) methyl) -6- (dimethoxymethyl) 5-cyanopyrid-2-yl) -1-methylurea, the synthesis of Example 22 was accomplished.

MS m / z (ESI): 346 & 348 [M + 1]

^{1 H NMR (400 MHz, CDCl} 3) δ major product (22 '): 13.10 (s , 1H), 8.46 (s, 1H), 8.45 (s, 1H), 7.77 (d, J = 8.4 Hz, 1H) , 7.13 (d, J = 8.4 Hz, IH), 6.51 (s, IH), 5.29 (s, IH), 5.11-5.08 (m, 2H), 3.53 (s, 3H). By-product (22): 13.55 (s, 1H), 10.25 (s, 1H), 8.48 (s, 1H), 8.47 (s, 1H), 8.10 (d, J = 8.4 Hz, 1H), 7.35 (d, J = 8.4 Hz, 1H), 4.97 (s, 2H), 4.08-4.06 (m, 1H), 3.57 (s, 3H).

Example 23

(6-formyl-5- (piperidin-4-yl) pyrid-2-yl) 2-yl) -1-methylurea

Step 1

(methyl) amino) -2- (dimethoxymethyl) -5 ', 6'-dihydro- [3,4'-dipyridine] -1' (2 ' H ) -carboxylate

The compound 23a (0.20 g, 0.56 mmol), [1, 1 ' -bis (diphenylphosphino) ) Ferrocene] palladium chloride (90 mg, 0.11 mmol), t-butyl-4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan- -dihydro pyrid -1- (2 H) - mixing the carboxylate (0.34 g, 1.11 mmol), potassium carbonate (0.23 g, 1.67 mmol), water (1 mL) and dioxane (5 mL), and nitrogen The mixture was diluted with water, extracted with ethyl acetate (50 mL x 3), and the organic phase was washed with saturated brine (50 mL x 2). The organic phase The residue was purified via silica gel chromatography (petroleum ether / ethyl acetate 84:16) to give the target product t-butyl-6 - ((t- Butoxycarbonyl) (methyl) amino) -2- ( Dimethoxymethyl) -5 ', 6'-dihydro- [3,4'-di-pyridin] -1' (2 'H) - a-carboxylate 23b (0.13 g, colorless oil) was obtained in 51% yield .

MS m / z (ESI): 464 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 7.64 (d, J = 8.4 Hz, 1H), 7.41 (d, J = 8.4 Hz, 1H), 5.67-5.65 (m, 1H), 5.54 (s, 1H) , 4.07 (s, 2H), 3.65 (t, J = 5.2 Hz, 2H), 3.46 (s, 6H), 3.45 (s, 3H), 2.40-2.38 (m, 2H), 1.53 (s, 9H), 1.52 (s, 9 H).

Step 2

2- (dimethoxymethyl) pyrid-3-yl) piperidine-l-carboxylate < / RTI >

Compound (1) Synthesis of t-butyl-6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl) -5 ', 6'-dihydro- [3,4'-dipyridine] '(2' H) - carboxylate 23b (0.13 g, 0.28 mmol) , palladium on carbon (26 mg, 20%), methanol (3 mL) and stirred for 16 hours in ethyl mixing acetate (2 mL), and room temperature Respectively. The mixture was filtered and eluted under reduced pressure to give the target product t-butyl-4- (6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl) pyrid- Piperidine-1-carboxylate 23c (0.13 g, colorless oil) as a crude product.

MS m / z (ESI): 466 [M + 1].

Step 3

6- (dimethoxymethyl) -N -methyl-5- (piperidin-4-yl) pyridin-

Compound 23c (0.13 mmol) was added to a solution of t-butyl-4- (6 - ((t-butoxycarbonyl) (methyl) amino) -2- (dimethoxymethyl) pyrid- g, 0.28 mmol), trifluoroacetic acid (1 mL) and dichloromethane (4 mL) were mixed and stirred at room temperature for 6 hours. The mixture was eluted under reduced pressure to give 23d (95 mg, pale yellow solid) of the target product 6- (dimethoxymethyl) -N -methyl-5- (piperidin- 4- yl) pyridin- 2- amine trifluoroacetate salt. ≪ / RTI > as crude product.

MS m / z (ESI): 266 [M + 1].

Step 4

4- (2- (dimethoxymethyl) -6- (methylamino) pyrid-3-yl) piperidine-1-carboxylate

Compound 6 (dimethoxy-methyl) - N - methyl-5- (piperidin-4-yl) pyridin-2-amine trifluoroacetic acetate salt 23d (95 mg, 0.25 mmol) , 2-t- butyl 2 Carbonitrile (82 mg, 0.38 mmol), triethylamine (76 mg, 0.75 mmol) and dichloromethane (4 mL) were mixed and stirred at room temperature for 6 hours. The mixture was quenched with 20 mL of water, extracted with ethyl acetate (20 mL x 3) and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 3: 1) to give the target product t-butyl-4- (2- (dimethoxymethyl) -6- (methylamino) -Yl) piperidine-1-carboxylate 23e (80 mg, white solid) in 65% yield.

MS m / z (ESI): 366 [M + 1].

Step 5

1-carboxylate < / RTI > was prepared by reacting t-butyl-4- (2- (dimethoxymethyl) -6- (methyl (phenoxycarbonyl) amino)

Compound 23e (40 mg, 0.11 mmol), diphenyl carbonate (prepared according to the procedure described for the synthesis of t-butyl 4- (2- (dimethoxymethyl) -6- 47 mg, 0.22 mmol), lithium hexamethyldisilazide (0.33 mL, 0.33 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran (6 mL) were mixed and stirred at 0 ° C for 0.5 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 2: 1) to give the target product t-butyl-4- (2- (dimethoxymethyl) -6- (methyl (phenoxycarbonyl) Amino) pyrid-3-yl) piperidine-l-carboxylate 23f (20 mg, white solid) in 38% yield.

MS m / z (ESI): 486 [M + 1].

Step 6

yl) -1- methylureido) -2- (dimethoxymethyl) pyrid-3-yl) thiophene- 1-carboxylate

Compound 23f (20 mg, 0.04 mmol) was added to a solution of t-butyl-4- (2- (dimethoxymethyl) -6- (methyl (phenoxycarbonyl) amino) pyrid- ), 6-amino-4-chloronicotinonitrile (12 mg, 0.08 mmol), lithium hexamethyldisilazide (0.12 mL, 0.12 mmol, 1 M solution in tetrahydrofuran) and tetrahydrofuran And the mixture was stirred at room temperature for 1 hour. The mixture was quenched with 10 mL of saturated ammonium chloride solution, extracted with ethyl acetate (20 mL x 3), and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1.5: 1) to give the target product t-butyl-4- (6- (3- (4-chloro-5-cyanopyrid- Yl) piperidine-1-carboxylate carboxylate (10 mg, white solid) in 45% yield, MS (m / z) .

MS m / z (ESI): 545 & 547 [M + 1].

Step 7

yl) -1-methylureido) -2- (dimethoxy-ethyl) -piperidine-l- Methyl) pyrid-3-yl) piperidine-1-carboxylate

2- (Dimethoxymethyl) pyrid-3-yl) -methanone [0215] < EMI ID = (10 mg, 0.02 mmol), 2-methoxyethylamine (3 mg, 0.06 mmol), diisopropylethylamine (5 mg, 0.06 mmol) and N, N -dimethylacetate Amide (0.4 mL) were mixed and stirred at 50 < 0 > C for 16 hours. The mixture was diluted with 10 mL of water, extracted with ethyl acetate (20 mL x 2), and the organic phase washed with saturated brine (20 mL x 2). The organic phase was dried over anhydrous sodium sulfate and filtered to remove the drying agent. The residue was purified through a silica gel plate for purification (petroleum ether / ethyl acetate 1.5: 1) to give the target product t-butyl-4- (6- (3- (5-cyano- 3-yl) piperidine-l-carboxylate 23h (6 mg, white solid) was added to a solution of 2-amino- ≪ / RTI > in 56% yield.

MS m / z (ESI): 584 [M + 1].

Step 8

(6-formyl-5- (piperidin-4-yl) pyrid-2-yl) 2-yl) -1-methylurea

Methyl-ureido) -2- (dimethylamino) pyrid-2-yl) -1- (6 mg, 0.01 mmol), hydrochloric acid (0.8 mL, 37%), water (1 mL) and tetrahydrofuran (2 mL) were added to a solution of And the mixture was stirred at room temperature for 1 hour. The mixture was eluted under reduced pressure to give the target product 3- (5-cyano-4 - ((2-methoxyethyl) amino) pyrid- Yl) pyrid-2-yl) -1-methylurea hydrochloride 23 (4 mg, white solid) in 89% yield.

MS m / z (ESI): 438 [M + 1] <

^{1 H NMR (400 MHz, CD} 3 OD) δ 8.40 (s, 1H), 8.01 (d, J = 8.4 Hz, 1H), 7.37 (d, J = 7.6 Hz, 1H), 6.92 (s, 1H), 2H), 3.19-3.15 (m, 1H), 2.12- (m, 2H), 3.02-3.40 (m, 1.95 (m, 4H).

Example 24

( S ) -3- (5-cyano-4 - ((1-methoxyprop-2-yl) oxy) Methyl-2-carbonylpiperazin-1-yl) methyl) pyrid-2-yl) -1-methylurea

Example 24 was synthesized with reference to the operating sequence of Example 18, except for replacing ( R ) -1-methoxypropan-2-ol with ( S ) -1-methoxypropan- .

MS m / z (ESI): 496 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.31 (s, 1H), 10.26 (s, 1H), 8.34 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.7Hz, 1H) , 7.29 (d, J = 8.7 Hz, 1H), 5.10 (s, 2H), 4.99-4.74 (m, 1H), 3.73-3.55 ), 3.37 (t, J = 5.3Hz, 2H), 3.20 (s, 2H), 2.67 (t, J = 5.3Hz, 2H), 2.36 (s, 3H), 1.41 (d, J = 6.3Hz, 3H ).

Example 25

( R ) -3- (5-cyano-4 - ((1-hydroxyprop-2-yl) oxy) pyrid- Methyl-2-carbonylpiperazin-1-yl) methyl) pyrid-2-yl) -1-methylurea

( R ) -3- (5-cyano-4 - ((1-methoxyprop-2-yl) oxy) pyrid- Methyl) urea-2-yl) -1-methylurea 18 (4.0 g, 8 mmol) and dichloromethane (80 mL) were mixed. In it, boron tribromide (20.2 g, 81 mmol) was added dropwise in an ice-salt bath. After the addition, the ice-salt bath was removed and the mixture was further stirred at room temperature for 30 minutes. The mixture was quenched with slowly poured ice water (300 mL) in it, adjusted to pH 8-9 using an aqueous saturated sodium carbonate solution (200 mL) and extracted with dichloromethane (150 mL x 3). The organic phases were combined, dried over anhydrous sodium sulfate, filtered to remove the drying agent and eluted under reduced pressure to give a crude product which was subjected to flash column chromatography (dichloromethane: methanol = 20: 1) to give the target product ( R ) -3- (5-cyano-4 - ((1-hydroxyprop-2-yl) oxy) pyrid- Yl) methyl) pyrid-2-yl) -1-methylurea 25 (2.3 g, 4.8 mmol, white solid) in 60% yield.

MS m / z (ESI): 482 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.36 (s, 1H), 10.26 (s, 1H), 8.35 (s, 1H), 7.99 (s, 1H), 7.94 (d, J = 8.5Hz, 1H) , 7.30 (d, J = 8.5Hz , 1H), 5.10 (s, 2H), 4.88-4.76 (m, 1H), 3.91-3.78 (m, 2H), 3.53 (s, 3H), 3.42-3.38 (s 2H), 3.20 (s, 2H), 2.75-2.63 (m, 2H), 2.36 (s, 3H), 1.41 (d, J = 6.0 Hz, 3H).

Example 26

( S ) -3- (5-cyano-4 - ((1 -hydroxyprop-2-yl) oxy) pyrid- Methyl-2-carbonylpiperazin-1-yl) methyl) pyrid-2-yl) -1-methylurea

In step 1 (R) -3- (5- cyano-4 - ((1-methoxy-prop-2-yl) oxy) pyrid-2-yl) -1- (6-formyl-5 ( S ) -3- (5-cyano-4 - ((1- (2-fluoro- Yl) oxy) pyrid-2-yl) -1- (6-formyl-5- -2-yl) -l-methylurea, < / RTI >

MS m / z (ESI): 482 [M + 1] <

^{1 H NMR (400 MHz, CDCl} 3) δ 13.37 (s, 1H), 10.26 (s, 1H), 8.34 (s, 1H), 7.97 (s, 1H), 7.95 (d, J = 8.8 Hz, 1H) , 7.32 (d, J = 8.8 Hz, 1H), 5.11 (s, 2H), 4.91-4.74 (m, 1H), 3.96-3.76 2H), 3.22 (s, 2H), 2.79-2.62 (m, 2H), 2.38 (s, 3H), 1.42 (d, J = 6.0 Hz, 3H).

Biological experiment

FGFR4 activity inhibition test

The effect of compounds according to the invention on the activity of fibroblast growth factor receptor 4 (FGFR4) was evaluated by in vitro kinase assay.

The experimental method is summarized as follows:

The in vitro activity of FGFR4 was determined by analyzing the level of phosphorylation of the substrate in the kinase reaction by the HTRF kinase assay kit. Reaction buffer to components: 5 times diluted enzyme buffer / kinase 5X (Cisbio, Cat. No. 62EZBFDD) (main component: 50 mM HEPES, pH 7.0) , 5 mM of MgCl _2, was done with DTT of 1 mM; The human recombinant FGFR4 catalytic structural domain protein (amino acid 460-802) was commercially available from Tsinghua Protein Research Technology Center and was diluted with 0.5 ng / μL of kinase solution using reaction buffer; Substrate The reaction solution consisted of a biotin labeled tyrosine kinase substrate (Cisbio, catalog number 62TK0PEC) diluted to 500 nM with the reaction buffer, and 90 μM ATP, and the assay solution was an assay buffer (Cisbio, catalog number 62SDBRDF) use was made of the Eu ³⁺ labeled cage (cage-shaped) antibody (Cisbio, Cat. No. 61T66KLB), and streptavidin labeled XL665 of 31.25 nM (Cisbio, Cat. No. 610SAXLB) diluted to 0.125 ng / μL .

The compound was dissolved in 100% DMSO and diluted to 100 [mu] M and then diluted 4-fold-series to a minimum concentration of 0.0061 [mu] M using DMSO and then added to each concentration point using reaction buffer 40-fold dilution. If the IC ₅₀ value of the compound is very low, the initial concentration of the compound can be reduced.

4 μL of the compound solution and 2 μL of the FGFR4 kinase solution were added into a 384 well assay plate (Thermo, catalog number 264706), mixed homogeneously, and then incubated at room temperature for 15 minutes; Subsequently, 4 μL of substrate reaction solution was added thereto, and the reaction mixture was incubated at room temperature for 60 minutes; An equal volume of 10 [mu] L of assay solution to the reaction was added thereto, homogeneously mixed, and then allowed to stand at room temperature. After 60 minutes, the enzyme reaction was terminated by EDTA in the assay solution, and at the same time the phosphorylated product was identified by both Eu3 ⁺ labeled cage-type antibody (donor) and streptavidin-labeled XL665 antibody (receptor) . After excitation with the laser, donors and receptors close to each other underwent energy resonance transfer, and the energy transferred from the donor (620 nm) to the acceptor (665 nm) could be detected with Envision. The ratio of 665/620 was positively correlated with the degree of substrate phosphorylation, thereby detecting FGFR4 kinase activity. In this experiment, the group to which no protein was added was used as a negative control (100% inhibition), and the group with protein but no compound was used as a positive control (0% suppression). The percent inhibition of this compound for FGFR4 activity could be calculated using the following equation:

Inhibition percentage = 100 - 100 * (signal _compound - signal _{negative control} ) / (signal _{positive control} - signal _{negative control} )

The IC ₅₀ values of the compounds were calculated from 10 concentration points using XLfit (ID Business Solutions Ltd., UK) by the following equation:

Y = Bottom + (Top-Bottom) / (1 + 10 ^ (LogIC ₅₀ -X) * slope factor)

Where Y is the percent inhibition, Bottom is the bottom plateau of the curve (bottom stagger of the S curve), Top is the top plateau of the curve (top stagger of the S curve) Is the logarithmic value of the compound concentration to be measured.

FGFR1 activity inhibition test

The effect of compounds according to the invention on the activity of fibroblast growth factor receptor 1 (FGFR1) was evaluated by in vitro kinase assay.

The experimental method is summarized as follows:

The in vitro activity of FGFR1 was determined by analyzing the level of phosphorylation of the substrate in the kinase reaction by the HTRF kinase assay kit. Reaction buffer to components: 5 times diluted enzyme buffer / kinase 5X (Cisbio, Cat. No. 62EZBFDD) (main component: 50 mM HEPES, pH 7.0) , 5 mM of MgCl _2, was done with DTT of 1 mM; Human recombinant FGFR1 catalytic structural domain protein (amino acids 308-731) was purified by the company itself and diluted with kinase solution of 0.6 ng / [mu] L using reaction buffer; The substrate reaction solution consisted of a biotin-labeled tyrosine kinase substrate (Cisbio, Cat. No. 62TK0PEC) diluted to 400 nM with the reaction buffer, and 40 μM ATP, and the assay solution consisted of assay buffer (Cisbio, catalog number 62SDBRDF) use was made of the Eu ³⁺ labeled antibody cage (Cisbio, Cat. No. 61T66KLB), and streptavidin labeled XL665 (Cisbio, Cat. No. 610SAXLB) of 25 nM diluted to 0.125 ng / μL.

The compound was dissolved in 100% DMSO and diluted to 1 mM and then diluted 4-fold with a minimum concentration of 0.0061 [mu] M using DMSO and then diluted 40 times with each concentration point using the reaction buffer. If the IC ₅₀ value of the compound is very low, the initial concentration of the compound can be reduced.

4 μL of the compound solution and 2 μL of the FGFR1 kinase solution were added into a 384 well assay plate (Thermo, catalog number 264706), mixed evenly, and then incubated at room temperature for 15 minutes; Subsequently, 4 μL of substrate reaction solution was added thereto, and the reaction mixture was incubated at room temperature for 60 minutes; An equal volume of 10 [mu] L of assay solution to the reaction was added thereto, homogeneously mixed, and then allowed to stand at room temperature. After 60 minutes, the enzyme reaction was terminated by EDTA in the assay solution, and at the same time the phosphorylated product was identified by both Eu3 ⁺ labeled cage-type antibody (donor) and streptavidin-labeled XL665 antibody (receptor) . After excitation with the laser, the donors and receptors close to each other experienced resonant energy transfer, and the energy transferred from the donor (620 nm) to the acceptor (665 nm) could be detected with Envision. The ratio of 665/620 was positively correlated with the degree of substrate phosphorylation, thereby detecting FGFR4 kinase activity. In this experiment, the group to which no protein was added was used as a negative control (100% inhibition), and the group with protein but no addition of the compound was used as a positive control (0% inhibition). The percent inhibition of this compound for FGFR1 activity could be calculated using the following equation:

Inhibition percentage = 100 - 100 * (signal _compound - signal _{negative control} ) / (signal _{positive control} - signal _{negative control} )

IC ₅₀ values of the compounds were calculated from 10 concentration points using XLfit (ID Business Solutions Ltd., UK) by the following equation:

Y = Bottom + (Top-Bottom) / (1 + 10 ^ (LogIC ₅₀ -X) * slope factor)

Where Y is the percent inhibition, Bottom is the bottom cone of the curve (bottom cone of the S curve), Top is the top cone of the curve (top cone of the S curve) and X is the logarithm of the compound concentration being measured .

FGFR2 activity inhibition test

The effect of compounds according to the invention on the activity of fibroblast growth factor receptor 2 (FGFR2) was evaluated by in vitro kinase assay.

The experimental method is summarized as follows:

The in vitro activity of FGFR2 was determined by analyzing the level of phosphorylation of the substrate in the kinase reaction by the HTRF kinase assay kit. The reaction buffer consisted of the following components: 5X Diluted Enzyme Buffer / Kinase 5X (Cisbio, catalog number 62EZBFDD) (major constituent: 50 mM HEPES, pH 7.0), 5 M MgCl ₂ , 1 mM DTT; Human recombinant FGFR2 catalytic structural domain protein (amino acids 400-821) was commercially available from Beijing Sino Biological Inc. and diluted with 0.045 ng / μL kinase solution using reaction buffer; The substrate reaction solution consisted of a biotinylated tyrosine kinase substrate diluted to 800 nM (Cisbio, Cat. No. 62 TKOPEC) using reaction buffer and 50 μM ATP, and the assay solution consisted of assay buffer (Cisbio, catalog number 62SDBRDF) use was made of the Eu ³⁺ labeled antibody cage (Cisbio, Cat. No. 61T66KLB), and streptavidin labeled XL665 (Cisbio, Cat. No. 610SAXLB) of 50 nM diluted to 0.125 ng / μL.

The compound was dissolved in 100% DMSO and diluted to 100 [mu] M, then serially diluted 4 times with a minimum concentration of 0.0061 [mu] M using DMSO and then diluted 40 fold at each concentration point using the reaction buffer. If the IC ₅₀ value of the compound is very low, the initial concentration of the compound can be reduced.

4 [mu] L of compound solution and 2 [mu] L of FGFR2 kinase solution are added into 384 well assay plates (Thermo, catalog number 264706), mixed homogeneously and then incubated at room temperature for 15 minutes; Subsequently, 4 μL of substrate reaction solution was added thereto, and the reaction mixture was incubated at room temperature for 60 minutes; An equal volume of 10 [mu] L of assay solution to the reaction was added thereto, homogeneously mixed, and then allowed to stand at room temperature. After 60 minutes, the enzyme reaction was terminated by EDTA in the assay solution, and at the same time the phosphorylated product was identified by both Eu3 ⁺ labeled cage-type antibody (donor) and streptavidin-labeled XL665 antibody (receptor) . After excitation with the laser, the donors and receptors close to each other experienced resonant energy transfer, and the energy transferred from the donor (620 nm) to the acceptor (665 nm) could be detected with Envision. The ratio of 665/620 was positively correlated with the degree of substrate phosphorylation, thereby detecting FGFR2 kinase activity. In this experiment, the group to which no protein was added was used as a negative control (100% inhibition), and the group with protein but no compound was used as a positive control (0% suppression). The percent inhibition of this compound for FGFR2 activity could be calculated using the following equation:

Inhibition percentage = 100 - 100 * (signal _compound - signal _{negative control} ) / (signal _{positive control} - signal _{negative control} )

The IC ₅₀ values of the compounds were calculated from 10 concentration points using XLfit (ID Business Solutions Ltd., UK) by the following equation:

Y = Bottom + (Top-Bottom) / (1 + 10 ^ (LogIC ₅₀ -X) * slope factor)

Where Y is the percent inhibition, Bottom is the bottom cone of the curve (bottom cone of the S curve), Top is the top cone of the curve (top cone of the S curve) and X is the logarithm of the compound concentration being measured .

FGFR3 activity inhibition test

The effect of compounds according to the invention on the activity of fibroblast growth factor receptor 3 (FGFR3) was evaluated by in vitro kinase assay.

The experimental method is summarized as follows:

The in vitro activity of FGFR3 was determined by analyzing the level of phosphorylation of the substrate in the kinase reaction by the HTRF kinase assay kit. Reaction buffer to components: 5 times diluted enzyme buffer / kinase 5X (Cisbio, Cat. No. 62EZBFDD) (main component: 50 mM HEPES, pH 7.0) , 5 mM of MgCl _2, was done with DTT of 1 mM; Human recombinant FGFR3 catalytic structural domain protein (amino acids 399-806) was commercially available from Sino Biological Inc. and diluted with 0.3 ng / μL of kinase solution using reaction buffer; The substrate reaction solution consisted of a biotin-labeled tyrosine kinase substrate diluted to 1000 nM (Cisbio, Cat. No. 62 TKOPEC) with reaction buffer and 90 μM ATP, and the assay solution was an assay buffer (Cisbio, catalog number 62SDBRDF) use was made of the Eu ³⁺ labeled antibody cage (Cisbio, Cat. No. 61T66KLB), and streptavidin labeled XL665 (Cisbio, Cat. No. 610SAXLB) of 62.5 nM diluted to 0.125 ng / μL.

The compound was dissolved in 100% DMSO and diluted to 100 [mu] M, then serially diluted 4 times with a minimum concentration of 0.0061 [mu] M using DMSO and then diluted 40 fold at each concentration point using the reaction buffer. If the IC ₅₀ value of the compound is very low, the initial concentration of the compound can be reduced.

4 [mu] L of compound solution and 2 [mu] L of FGFR3 kinase solution are added into 384 well assay plates (Thermo, catalog number 264706), mixed homogeneously and then incubated at room temperature for 15 minutes; Subsequently, 4 μL of substrate reaction solution was added thereto, and the reaction mixture was incubated at room temperature for 60 minutes; An equal volume of 10 [mu] L of assay solution to the reaction was added thereto, homogeneously mixed, and then allowed to stand at room temperature. After 60 minutes, the enzyme reaction was terminated by EDTA in the assay solution, and at the same time the phosphorylated product was identified by both Eu3 ⁺ labeled cage-type antibody (donor) and streptavidin-labeled XL665 antibody (receptor) . After excitation with the laser, the donors and receptors close to each other experienced resonant energy transfer, and the energy transferred from the donor (620 nm) to the acceptor (665 nm) could be detected with Envision. The ratio of 665/620 was positively correlated with the degree of substrate phosphorylation, thereby detecting FGFR3 kinase activity. In this experiment, the group to which no protein was added was used as a negative control (100% inhibition), and the group with protein but no compound was used as a positive control (0% suppression). The percent inhibition of the compound for FGFR3 activity could be calculated using the following equation:

Inhibition percentage = 100 - 100 * (signal _compound - signal _{negative control} ) / (signal _{positive control} - signal _{negative control} )

The IC ₅₀ values of the compounds were calculated from 10 concentration points using XLfit (ID Business Solutions Ltd., UK) by the following equation:

Y = Bottom + (Top-Bottom) / (1 + 10 ^ (LogIC ₅₀ -X) * slope factor)

Where Y is the percent inhibition, Bottom is the bottom cone of the curve (bottom cone of the S curve), Top is the top cone of the curve (top cone of the S curve) and X is the logarithm of the compound concentration being measured .

Biological Assay Examples: A: <10 nM, B: 10-100 nM, C: 100-1000 nM, D:> 1000 nM, ND:

The compounds according to the present invention have a selective inhibitory effect on FGFR4.

Hep3B cell proliferation inhibition test

The effect of compounds according to the present invention on Hep3B cell proliferation was evaluated by a luminescence cell viability test.

The experimental method is summarized as follows:

Indicator ATP of active cellular metabolism was detected by a unique stable luciferase using CTG (CellTiter-Glo) assay kit. The luminescence signal generated in the test was directly proportional to the count of active cells in the medium. To detect the cell proliferation of Hep3B.

The CellTiter-Glo agonist (Promega, G7572) consisted of CellTiter-Glo lyophilized powder and CellTiter-Glo buffer, and the lyophilized powder was dissolved in the buffer used.

Hep3B cells (ATCC, HB-8064) (cell source: Shanghai Academy of Life Sciences, Chinese Academy of Sciences) were mixed with 10% FBS (GBICO, 10099-141) and 100 units / ml of mycillin And cultured in DMEM complete medium (Thermofisher, 11995073) containing mixed solution (Thermofisher, 15140122). When the cell coverage reaches 80-90% of the culture vessels, the cells are digested and blotted with 0.25% pancreatin (EDTA) (Thermofisher, 25200056) (Thermofisher, 164610) so as to have 1000 cells in a medium (27 μl of DMEM complete medium) and the 384-well plate was placed in an incubator at 37 ° C and 5% CO ₂ overnight ( 18 to 20 hours). The compound was dissolved in 100% DMSO and diluted to 100 [mu] M and then serially diluted 4 times with a minimum concentration of 0.0061 [mu] M using DMSO and each concentration point was diluted 50-fold using FBS-free DMEM medium . If the IC ₅₀ value of the compound is very low, the initial concentration of the compound can be reduced. After overnight incubation, 3 [mu] l of DMEM diluted compound was added to each well, gently centrifuged, and mixed evenly, where 10 [mu] M BLU9931 group served as negative control (100% inhibition) % DMSO group was added to act as a positive control (0% inhibition). For further incubation, these 384-well plates were placed in an incubator at 37 ° C and 5% CO ₂ , removed after 72 hours, and allowed to stand at room temperature for 30 minutes. The CTG agonist was also withdrawn and equilibrated to room temperature. 15 [mu] l of CTG agonist was added to each well, left on a shaker to ensure sufficient cell lysis and gently shaken for 3 minutes. After standing for 10 minutes to stabilize the emission signal, the emission signal was read by EnVision (Perkin Elmer).

The percent inhibition of the compound for Hep3B cell proliferation can be calculated using the following equation:

Inhibition percentage = 100 - 100 * (signal _compound - signal _{negative control} ) / (signal _{positive control} - signal _{negative control} )

The IC ₅₀ values of the compounds were calculated from eight concentration points using XLfit (ID Business Solutions Ltd., UK) by the following equation:

Y = Bottom + (Top-Bottom) / (1 + 10 ^ (LogIC ₅₀ -X) * slope factor)

Where Y is the percent inhibition, Bottom is the bottom cone of the curve (bottom cone of the S curve), Top is the top cone of the curve (top cone of the S curve) and X is the logarithm of the compound concentration being measured .

Biological Assay Examples: A: <50 nM, B: 50-100 nM

From the above table, it can be seen that the compound according to the present invention has an excellent inhibitory effect on Hep3B cell proliferation.

Claims (10)

Compounds as shown in formula (I), isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof:

(I)
Wherein ring A and R are each independently selected from the group consisting of substituted or unsubstituted aryl and heteroaryl groups, wherein when substituted, A or R may be substituted at any position with one or more substituents, substituent is independently hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, formyl, -C (O) R ^1, carboxyl, alkenyl , alkynyl, -OR ¹ and -NR ² is selected from the group consisting of R ^3, wherein said alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1- C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR 5 R 6, - ^{C (O) R 4, -NR} 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR 5 S (O) ^{mR 4, -SR 4, -NR 4} S (O) mNR 5 R 6 , and -S (O) 1 or more selected from the group consisting of mNR ⁵ R ⁶ Optionally, (optionally) substituted with a substituent;
X is a divalent ^{CR 7 R 8, NR 7,} O and S selected from the group consisting of radicals;
Y is -C (O) - is selected from, -S (O) a group consisting of ^{m- -, -C (= NR 9} );
Wherein R ¹ , R ² , R ³ , R ⁴ , R ⁵ and R ⁶ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3-8 membered monocyclic heterocyclyl, monocyclic heteroaryl Or monocyclic aryl, alkenyl and alkynyl, wherein R ² and R ³ , or R ⁵ and R ⁶ together with the N atom to which they are attached form a 3- to 7-membered heterocyclyl group Can be; And R ⁷ and R ⁸ together with the C atom to which they are attached may form a 3- to 8-membered cycloalkyl group or a 3- to 8-membered monocyclic heterocyclyl group;
R ⁷ and R ⁸ are each independently hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, formyl, -C (O) R ¹ , carboxyl, alkenyl, alkynyl, -OR ¹ and -NR are selected from the group consisting of R ^{2 3,} wherein said alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR ^{5 R 6, -C (O)} R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR ⁵ S (O) mR ⁴ , -SR ⁴ , -NR ⁴ S (O) mNR ⁵ R ⁶ and -S (O) mNR ⁵ R ⁶ ;
R ⁹ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocyclyl, aryl, heteroaryl, formyl, C (O) R ¹ , alkenyl and alkynyl selected and wherein the group alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, -OR ^4, -OC ^{(O) NR 5 R 6,} -C (O) OR 4, -C (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, ^{-NR 4 C (O) NR 5} R 6, -S (O) mR 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , -S (O ) mNR &lt; ⁵ &gt; R &lt; ^{6 &} gt ;;
m is 1 or 2; The compound of claim 1, wherein the compound represented by formula (I) is represented by formula (II): wherein R 1, R 2, R 3, R 4,

(II)
In this formula,
Z ¹ , Z ² and Z ³ are each independently selected from the group consisting of CR ^Z1 , CR ^Z2 , CR ^Z3 or N,
When Z ¹ is N, then Z ² and Z ³ are not simultaneously N;
When Z ² is N, then Z ¹ and Z ³ are not simultaneously N;
When Z ³ is N, then Z ¹ and Z ² are not simultaneously N;
R ^Z1 , R ^Z2 and R ^Z3 are each independently selected from the group consisting of hydrogen, halogen, cyano, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered heterocyclyl, aryl, heteroaryl, ) R ^1, carboxyl, alkenyl, alkynyl, -OR ¹ and -NR are selected from the group consisting of R ^{2 3,} wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) OR 4, -C (O) NR 5 R 6 ^{, -C (O) R 4,} -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, -S (O) mR 4, -NR 5 S ( ^{O) mR 4, -SR 4,} -NR 4 S (O) mNR 5 R 6 , -S (O) is optionally substituted with one or more substituents selected from the group consisting of mNR ⁵ R ^6;
X, Y, R and R &lt; ^1-9 &gt; are as defined in ^claim 1;
If Z ¹ is CCH ₂ OH, CCH ₂ COOH, or C- (4- piperidine), compound (2-1), (2-2) and (2-3) has isomers (2-1A), ( 2-2A) and (2-3A): &lt; RTI ID = 0.0 &gt;

. The compound according to claim 1 or 2, wherein the compound represented by formula (I) is a compound represented by formula (IIIa), (IIIb), (IIIc), (IIId), (IIIe) Compounds, isomers, prodrugs, stable isotope derivatives or pharmaceutically acceptable salts thereof:

In this formula,
R ^Z1, R ^Z2, R ^Z3, R ¹⁰ and R ¹¹ are each independently hydrogen, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, aryl, heteroaryl, formyl wheat, -C (O) R ^1, carboxyl, alkenyl, alkynyl, -OR ¹ and -NR are selected from the group consisting of R ^{2 3,} wherein said alkyl, alkenyl, alkynyl, heterocyclyl, heterocyclyl , aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, -C (O) ^{OR 4, -C (O) NR} 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 R 6, - ^{S (O) mR 4, -NR} 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , -S (O) at least one selected from the group consisting of mNR ⁵ R ⁶ Lt; / RTI &gt;
R ⁷ is independently selected from the group consisting of H, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6 ^{, -C (O) OR 4,} -C (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) consisting of ^{NR 5 R 6, -S (O} ) mR 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , and -S (O) mNR ⁵ R ⁶ Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
R ¹ to R ⁶ are defined as in claim 1;
The R ² and R ³ , or R ⁵ and R ⁶ , together with the N atom to which they are attached, may form a 3- to 8-membered heterocyclyl group. 4. A compound according to any one of claims 1 to 3, wherein the compound as shown in formula (I) is of the formula (IV), an isomer thereof, a prodrug, a stable isotope derivative, Possible salts:

In this formula,
R ^Z1 and R ^Z2 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C7 cycloalkyl, 4-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl or monocyclic aryl, formyl, keto, carboxyl, cyano, oR ^1, and NR ² are selected from the group consisting of R ^3, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, hydroxy, C1-C4 Optionally substituted with one or more substituents selected from the group consisting of alkyl, C3-C7 cycloalkyl, 4 to 6 membered heterocyclyl, aryl or heteroaryl;
R ⁷ is selected from H, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic the group consisting of aryl, wherein said alkyl, heterocyclyl , heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered ^{heterocyclyl, -OR 4, -OC (O)} NR 5 R 6, - ^{C (O) OR 4, -C} (O) NR 5 R 6, -C (O) R 4, -NR 5 R 6, -NR 5 C (O) R 4, -NR 4 C (O) NR 5 ^{R 6, -S (O) mR} 4, -NR 5 S (O) mR 4, -SR 4, -NR 4 S (O) mNR 5 R 6 , -S (O) R ⁶ from the group consisting of ⁵ mNR Optionally substituted with one or more substituents selected;
R &lt; ¹⁰ &gt; is independently selected from the group consisting of hydrogen, halogen, halo C1-C4 alkyl and cyano;
R ¹¹ is independently selected from the group consisting of hydrogen, halogen, C 1 -C 4 alkyl, halo C 1 -C 4 alkoxy, C 1 -C 6 alkoxy, HO-C 1 -C 4 alkoxy, cyano, NR ² R ³ , C 1 -C 4 alkoxy C 1 -C 4 alkoxy, C1-C4 alkoxy halo C1-C4 alkoxy;
R ¹ , R ² and R ³ are each independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, Alkylthiol, and haloalkoxy substituted with hydroxy at any position;
R ⁴ to R ⁶ are defined as in claim 1. The compound according to any one of claims 1 to 4, wherein the compound represented by the formula (I) is a compound of the formula (V), an isomer thereof, a prodrug, a stable isotope derivative, Possible salts:

In this formula,
R ^Z1 and R ^Z2 are each independently selected from the group consisting of hydrogen, halogen, C1-C4 alkyl, C3-C7 cycloalkyl, 5-6 membered monocyclic heterocyclyl, 5-6 membered monocyclic heteroaryl or monocyclic aryl, Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with one or more substituents selected from the group consisting of halogen, hydroxy, Ci-C4 alkyl, 5-6 membered heterocyclyl, aryl or heteroaryl &Lt; RTI ID = 0.0 &gt; 1, &lt; / RTI &gt;
R ⁷ is selected from the group consisting of hydrogen, C 1 -C 4 alkyl and C 3 -C 6 cycloalkyl wherein said alkyl or cycloalkyl group is optionally substituted with one or more groups selected from the group consisting of C 1 -C 3 alkyl and 4-6 membered monocyclic heterocyclyl Optionally substituted with one or more of the above substituents;
R ¹¹ is selected from the group consisting of NR ² R ³ , C ¹ -C 3 alkoxy and -O (CH ₂ ) _0-1 -R ⁴ ; Wherein R ⁴ is independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, HO-C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl is selected from the group, wherein said alkyl, heterocyclyl, heterocyclyl, aryl or heteroaryl group, halogen, cyano, C1-C8 alkyl, C3-C8 heterocyclyl, 3- to 8-membered heterocyclyl, -OR ^{5, -OC (O) NR 5 R 6} , -C (O) OR 5, -C (O) NR 5 R 6, -C (O) R 5, -NR 5 R 6, -NR 5 C (O) R ^{6, -NR 7 C (O)} NR 5 R 6, -S (O) mR 5, -NR 5 S (O) mR 6, -SR 5, -NR 7 S (O) mNR 5 R 6 , -S (O) mNR &lt; ⁵ &gt; R &lt; ^{6 &} gt ;;
R ² and R ³ are independently selected from the group consisting of hydrogen, C 1 -C 8 alkyl, C 3 -C 8 cycloalkyl, 3 to 8 membered monocyclic heterocyclyl, monocyclic heteroaryl or monocyclic aryl, Wherein said alkyl, cycloalkyl, heterocyclyl, aryl or heteroaryl group is optionally substituted with at least one substituent selected from the group consisting of halogen, cyano, C1-C8 alkyl, C3-C8 cyclo , 3- to 8-membered ^{heterocyclyl, -OR 5, -OC (O)} NR 5 R 6, -C (O) OR 5, -C (O) NR 5 R 6, -C (O) R 5, - ^{NR 5 R 6, -NR 5 C} (O) R 6, -NR 7 C (O) NR 5 R 6, -S (O) mR 6, -NR 5 S (O) mR 6, -SR 5, - NR ⁷ S (O) mNR ⁵ R ⁶ and -S (O) mNR ⁵ R ⁶ ;
R ⁴ to R ⁶ are defined as in claim 1. The compound according to claim 1, wherein the compound represented by the formula (I) is the following isomer, prodrug, stable isotope derivative or pharmaceutically acceptable salt thereof:

A pharmaceutical composition comprising a compound according to any one of claims 1 to 6, an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent and excipient thereof A pharmaceutical composition. A compound according to any one of claims 1 to 6, an isomer thereof, a prodrug, a stable isotope derivative according to any one of claims 1 to 6, in the manufacture of a medicament for the treatment or prevention of FGFR and especially FGFR4 mediated diseases such as cancer, Or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7. A pharmaceutical composition comprising a therapeutically effective amount of a compound according to any one of claims 1 to 6, an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 7, Comprising administering to a mammal in need thereof a therapeutically effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof, for the treatment or prophylaxis of FGFR and particularly FGFR4 mediated diseases such as cancer, particularly hepatocellular carcinoma. The use of a compound according to any one of claims 1 to 6, an isomer thereof, a prodrug, a stable isotope derivative or a pharmaceutically acceptable salt thereof in the treatment or prevention of FGFR and especially FGFR4 mediated diseases such as cancer, Salt, or a pharmaceutical composition according to claim 7.